Method for determination of onset risk of glaucoma

ABSTRACT

A method of determining the presence or the absence of a glaucoma risk by detecting in vitro an allele and/or a genotype of a single nucleotide polymorphism, comparing the allele and/or the genotype detected with at least one of an allele and/or a genotype with a high-risk allele, wherein the presence of a glaucoma risk is determined in a case where the allele detected is the high-risk allele, or the presence of a glaucoma risk is determined in a case where the genotype detected is a homozygote of the genotype comprising the high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or the presence of a glaucoma risk is determined in a case where the genotype detected is a homozygote of the genotype comprising the high-risk allele when the high-risk allele complies with a recessive genetic model.

TECHNICAL FIELD

The present invention relates to a method of detecting the presence of a single nucleotide polymorphism associated with the onset of glaucoma, or a single nucleotide polymorphism with a high onset risk of glaucoma, and a kit used in the detection method.

BACKGROUND ART

Glaucoma is a disease which causes a characteristic optic nerve cupping and an impairment in a visual field by retinal ganglion cell death. An elevation in an intraocular pressure is considered to be a major cause for the nerve cupping and the impairment in the visual field in glaucoma. On the other hand, there is also glaucoma in which an intraocular pressure is held within a normal range in statistical calculation, and even in this case, it is considered that glaucoma develops because the intraocular pressure is at a sufficiently high level for causing the impairment in a visual field for an individual.

The basic treatment for glaucoma is to maintain an intraocular pressure at a low level, and it is necessary to consider the causes for a high intraocular pressure in order to maintain a low intraocular pressure. Therefore, in the diagnosis of glaucoma, it is important to classify the types of glaucoma in accordance with the levels of intraocular pressures and causes therefor. As the causes for an elevation in an intraocular pressure, the presence or absence of closure of angle which is a major drainage pathway for an aqueous humor filling an eye is important. From these viewpoints, the primary glaucoma is roughly classified into the two groups of closed-angle glaucoma accompanying angle closure and open-angle glaucoma without accompanying angle closure. Among them, the open-angle glaucoma is classified into open-angle glaucoma, in a narrow sense, accompanying an elevation in an intraocular pressure, i.e. primary open-angle glaucoma, and normal tension glaucoma in which an intraocular pressure is held within a normal range.

It is known from old times that glaucoma is associated with inheritance. It is reported that 5 to 50% of individuals with open-angle glaucoma have a family history, and it is generally understood that 20 to 25% of individuals have hereditary causes. Based on these reports, studies on a search for a gene responsible for glaucoma are performed. As a result, it is reported that a mutation in myocilin (MYOC) gene is associated with open-angle glaucoma (See Patent Publication: 1), and that a mutation in optineurin gene (OPTN) is associated with normal tension glaucoma (See Non-Patent Publication: 1). However, all the genetic causes of glaucoma cannot be explained only by these genes, and the presence of unknown glaucoma-related genes is expected.

On the other hand, a single nucleotide polymorphism means that a substitution mutation in which a single base is changed into another base is found in base sequences of the genome of an individual, and the mutation exists in a certain frequency, generally a frequency of about 1% or more, in the population of an organism species. A single nucleotide polymorphism exists at intron or exon on genes, or any of the regions of the genome other than these.

-   Patent Publication 1: Japanese Patent-Laid Open No. 2000-306165 -   Non Patent Publication 1: Rezaie T and eleven others, Science, 2002,     295(5557), 1077-1079.

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

Generally, an intraocular pressure or an ocular fundus photograph is used as a simple examination for glaucoma; however, these examinations do not necessarily lead to a definite diagnosis for glaucoma. Usually, in addition to these, visual field examinations are performed; however, there are some disadvantages that the examination is carried out for a long period of time, causing burdens on patients, and that one must be accustomed to the examination, so that initial examination results have low reliability.

On the other hand, as mentioned above, the involvement of hereditary causes is strongly suspected in the onset of glaucoma, but critical responsible genes are not identified. On the other hand, even if the involvement of a single gene to the disease cannot be explained by a mutation or polymorphism, it is considered that there are numerous mutations or polymorphisms of a gene of which involvement to glaucoma is relatively moderate, and the involvement of hereditary causes to the onset of glaucoma can be explained by a combined action of each of these mutations or polymorphisms.

The inventors have remarked on a polymorphism on the genome, especially a single nucleotide polymorphism, in order to find a gene associated with glaucoma.

By finding polymorphisms involved in the onset of glaucoma, a person having the polymorphisms which are found in a high frequency in glaucoma patients is predicted to have a high onset risk of glaucoma in future even before the onset thereof. Also, the polymorphisms can be applied to screening of whether or not a visual field examination is required, in an early stage of glaucoma which is difficult to be detected by the simple determination of glaucoma, i.e. a method such as a measurement of intraocular pressure or an ocular fundus photograph, which is available to be diagnosed only by carrying out the visual field examination. In other words, a sample donor can take a preventive measure for the onset of glaucoma by knowing the onset risk of glaucoma, and in addition, a necessary measure for preventing visual constriction such as a definite diagnosis and an initiation of treatment at an early stage according to a precision examination can be taken; therefore, it is important to find a polymorphism involved in the onset of glaucoma.

An object of the present invention is to provide a method of detecting a single nucleotide polymorphism involved in the onset of glaucoma, thereby predicting an onset risk of glaucoma, and a kit used in the detection method.

Means to Solve the Problems

The present inventors have found a single nucleotide polymorphism associated with the onset of glaucoma by a comprehensive analysis of known polymorphic sites existing on the genome (autosome) in glaucoma patients and non-patients without a family history of glaucoma, and further found an allele identified in a high frequency in glaucoma patients and an opposite allele thereof, and a genotype identified in a high frequency in glaucoma patients, which is a combination of each of the alleles, in the single nucleotide polymorphism. Furthermore, the present inventors have found that a determination on whether or not a sample donor is a person who is more likely to suffer from the onset of glaucoma can be made at an even higher precision by performing the determination in a combination of these plural single nucleotide polymorphisms associated with the onset of glaucoma. Thus, the present invention has been perfected thereby.

Concretely, the present invention relates to:

[1] a method of determining the presence or the absence of a glaucoma risk, including the steps of:

detecting in vitro an allele and/or a genotype of a single nucleotide polymorphism which is located on a 31st base of a base sequence, in a sample from a subject, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto (step A), and

comparing the allele and/or the genotype detected in the step A with at least one of an allele and/or a genotype, containing a high-risk allele, in the base sequences shown in SEQ ID NOs: 203 to 514 (step B),

wherein the presence of a glaucoma risk is determined in a case where the allele detected in the step A is the high-risk allele, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in the step A is a homozygote of the genotype containing the high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in the step A is a homozygote of the genotype containing the high-risk allele when the high-risk allele complies with a recessive genetic model; [2] a method of determining the presence or the absence of a glaucoma risk, including the steps of:

detecting in vitro, in a sample from a subject, an allele and/or a genotype of a single nucleotide polymorphism which is located on a 31st base of a base sequence in a nucleic acid molecule, wherein the nucleic acid molecule comprises at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto (step C1), or

detecting in vitro, in a sample from a subject, an allele and/or a genotype of a single nucleotide polymorphism, using a nucleic acid molecule comprising a base sequence containing at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto (step C2), and

comparing the allele and/or the genotype detected in the step C1 or C2 with at least one nucleic acid molecule comprising an allele and/or a genotype, containing a high-risk allele, in the base sequences shown in the SEQ ID NOs: 203 to 514 (step D),

wherein the presence of a glaucoma risk is determined in a case where the allele detected in the step C1 or C2 is the high-risk allele, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in the step C1 or C2 is a homozygote of the genotype containing the high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in the step C1 or C2 is a homozygote of the genotype containing the high-risk allele when the high-risk allele complies with a recessive genetic model; [3] a kit of determining the presence or the absence of a glaucoma risk, containing

a nucleic acid molecule comprising at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partial sequence thereof, wherein the nucleic acid molecule comprises a single nucleotide polymorphism which is located on a 31st base of a base sequence, and/or

a nucleic acid molecule comprising a base sequence containing at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto,

wherein the kit is for use in detecting in vitro an allele and/or a genotype of a single nucleotide polymorphism in a sample from a subject; [4] a method of determining the presence or the absence of a glaucoma risk, including the following steps of: step (i): extracting a nucleic acid molecule from a sample from a subject, step (ii): detecting an allele of a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, for the nucleic acid molecule extracted in the step (i), and step (iii): determining the presence or the absence of a glaucoma risk, based on the allele detected in the step (ii); [5] use of a nucleic acid molecule for determining a glaucoma risk, wherein the nucleic acid molecule comprises at least one base sequence, the base sequence being a base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partial sequence thereof, wherein the nucleic acid molecule comprises an allele and/or a genotype of a single nucleotide polymorphism which is located on a 31st base of a base sequence; [6] a method of diagnosing glaucoma, including the steps of:

detecting in vitro an allele and/or a genotype of a single nucleotide polymorphism which is located on a 31st base of a base sequence, in a sample from a subject, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto (step E), and

comparing the allele and/or the genotype detected in the step E with at least one of an allele and/or a genotype, containing a high-risk allele, in the base sequences shown in SEQ ID NOs: 203 to 514 (step F),

wherein the subject is diagnosed as glaucoma in a case where the allele detected in the step E is the high-risk allele, or wherein the subject is diagnosed as glaucoma in a case where the genotype detected in the step E is a homozygote of the genotype containing the high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or wherein the subject is diagnosed as glaucoma in a case where the genotype detected in the step E is a homozygote of the genotype containing the high-risk allele when the high-risk allele complies with a recessive genetic model; and [7] a method of determining an onset risk of glaucoma, including the following steps of: step (I): determining the presence or the absence of the onset risk of glaucoma, with the method as defined in claim 3, step (II): determining that a further risk determination is needed, in a case where the presence of the onset risk is determined in the step (I) for any one of single nucleotide polymorphisms, and step (III): further determining the presence or the absence of the onset risk of glaucoma, with the method as defined in claim 5, in a case of being determined that a further risk determination is needed in the step (II).

Effects of the Invention

According to the method of the present invention, the presence or the absence of the onset risk of glaucoma in a sample donor can be determined, and further the level of the risk can be predicted, by analyzing an allele or a genotype of a single nucleotide polymorphism in the present invention contained in a nucleic acid molecule derived from the genome existing in a sample. A sample donor can be provided with a preventive measure for glaucoma, or can receive appropriate treatments, on the basis of this risk. In addition, according to the method of the present invention, a sample donor who is suspected of glaucoma, having an allele or a genotype containing a single nucleotide polymorphism in the genome that is identified in a high frequency in glaucoma patients, can be given a detailed examination on whether or not the donor is with early glaucoma, which is difficult to be determined sufficiently by an intraocular pressure or an ocular fundus photograph, and can be started with a treatment at an early stage in a case where the donor is diagnosed as glaucoma.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is a method of determining the presence or the absence of a glaucoma risk, including the step of detecting in vitro an allele and/or a genotype having at least one single nucleotide polymorphism using at least one single nucleotide polymorphism (hereinafter may be referred to as SNP) contained in a base sequence selected from the group consisting of specified base sequences or a complementary sequence thereto, wherein the method of determining the presence or the absence of a glaucoma risk further includes the step of:

comparing the allele and/or the genotype detected in the step with at least one of an allele and/or a genotype, containing a high-risk allele, in the specified base sequences, in a sample from a subject,

wherein the presence of a glaucoma risk is determined in a case where the detected allele is the high-risk allele, or wherein the presence of a glaucoma risk is determined in a case where the detected genotype is a homozygote of the genotype containing the high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or wherein the presence of a glaucoma risk is determined in a case where the detected genotype is a homozygote of the genotype containing the high-risk allele when the high-risk allele complies with a recessive genetic model. A great feature of the present invention resides in that a single nucleotide polymorphism associated with the onset of glaucoma is found, further that in the single nucleotide polymorphism, an allele identified in a high frequency in glaucoma patients and an opposite allele thereof, and a genotype, which is a combination of each of the alleles identified in a high frequency in glaucoma patients are found, and used. The polymorphism as used herein refers to a matter that a diversity is found in sequences of a specified location on the genome in a certain organism species, and a site at which the polymorphism exists (hereinafter also referred to as polymorphic site) refers to a site on the genome that a single nucleotide polymorphism is found.

In addition, the allele as used herein refers to each of types having a different base from each other that can be taken in a certain polymorphic site. The genotype as used herein refers to a combination of opposite alleles in a certain polymorphic site. Further, in a certain polymorphic site, there are three types for a genotype which is a combination of opposite alleles, wherein a combination of the same alleles is referred to as a homozygote, and a combination of different alleles is referred to as a heterozygote.

The opposite allele as used herein refers to another allele corresponding to a specified allele among the alleles constituting a certain single nucleotide polymorphism.

In the present invention, the single nucleotide polymorphism associated with glaucoma refers to a single nucleotide polymorphism associated with the onset of glaucoma or a single nucleotide polymorphism associated with the progression of glaucoma. In other words, the single nucleotide polymorphism associated with the onset of glaucoma refers to a single nucleotide polymorphism in which each allele or each genotype frequency in the single nucleotide polymorphism significantly differs in a statistical analysis at a given p-value between glaucoma patients and non-patients; and the single nucleotide polymorphism associated with the progression of glaucoma refers to a single nucleotide polymorphism in which each allele or each genotype frequency in the single nucleotide polymorphism significantly differs in a statistical analysis at a given p-value between the progressive glaucoma cases and the nonprogressive glaucoma cases.

In the present invention, the high-risk allele refers to an allele having a higher frequency in a glaucoma patient group than that of a non-patient group among each of the alleles of the single nucleotide polymorphism associated with glaucoma. On the other hand, in the present invention, the low-risk allele refers to an allele opposite to the high-risk allele in a certain polymorphic site.

In addition, the homozygote and the heterozygote of a genotype are defined in the same manner as in the high-risk allele and the low-risk allele. In other words, in certain polymorphic sites, a combination of high-risk alleles or low-risk alleles themselves is referred to a homozygote, and a combination of a high-risk allele and a low-risk allele is referred to as a heterozygote.

An embodiment where allele frequencies of the glaucoma patient group and the non-patient group are statistically compared is referred to as an allele model, and an embodiment where genotype frequencies thereof are compared is referred to as a genotype model. There are a dominant genetic model and a recessive genetic model in the genotype models, wherein the former means an embodiment where both a homozygote of high-risk alleles and a heterozygote are involved with the onset risk, and the latter means an embodiment where a homozygote of a high-risk allele is involved with the onset risk.

In the present invention, the glaucoma risk refers to a risk concerning glaucoma. The onset risk of glaucoma refers to a possibility of the future onset of glaucoma determined by susceptibility to a disease. In the present invention, the prediction of a risk refers to a determination of the presence or the absence of a future risk at the present stage, or determining the level of a future risk at the present stage.

Also, the glaucoma as used herein means preferably open-angle glaucoma (OAG) or normal tension glaucoma (NTG), and the open-angle glaucoma, when used without specifying otherwise, means primary open-angle glaucoma (POAG) in a narrow sense, without embracing normal tension glaucoma.

A method of identifying a single nucleotide polymorphism associated with glaucoma will be explained hereinbelow.

In the present invention, in selecting the single nucleotide polymorphism associated with glaucoma, in particular, a candidate single nucleotide polymorphism is selected by the steps including extracting a total DNA from blood of each of glaucoma patients diagnosed as primary open-angle glaucoma or normal tension glaucoma and non-patients diagnosed as not being with glaucoma and determined to have no family history of glaucoma according to a medical interview (also referred to as control individuals), and comparing allele or genotype frequencies of individual single nucleotide polymorphisms in the glaucoma patients and the non-patients using known single nucleotide polymorphisms of about 500,000 on the human genome as an index. Further, the allele or genotype frequencies of individual single nucleotide polymorphisms for the single nucleotide polymorphisms that are selected as candidates are obtained for glaucoma patients and non-patients that are different from the sample groups mentioned above. By combining these results, a single nucleotide polymorphism of which difference in frequencies is recognized with high statistical significance is found. Here, a group composed of the glaucoma patients is referred to as a glaucoma patient group, and a group composed of the non-patients is referred to as a non-patient group. By using the alleles or genotypes having a single nucleotide polymorphism associated with the onset of glaucoma found according to these analyses, the determination of the presence or the absence of the onset risk of glaucoma, and the prediction of the level of an onset risk can be enabled. Although the details will be explained in the section of Examples, a single nucleotide polymorphism associated with glaucoma disclosed in the present invention can be identified according to a method given below.

(Identification of Single Nucleotide Polymorphism Associated with Glaucoma)

First, a total DNA is extracted from blood of each of patients diagnosed as glaucoma and non-patients determined to have no family history of glaucoma. The total DNA in blood can be extracted by any known methods; for example, a DNA can be extracted by binding a DNA eluted by lysing cells to surfaces of magnetic beads coated with silica, and separating and collecting the DNA utilizing a magnetic force.

The kind of a base in a single nucleotide polymorphism in the extracted DNA sample, i.e. an allele having a single nucleotide polymorphism can be identified by any methods, including, for example, a method using an immobilized probe described later, or the like. Upon the identification, a probe used in the detection can be designed on the basis of the sequence information of a single nucleotide polymorphism of interest and surrounding sequences thereof. When the probe is designed, the sequence information obtained from the database for known single nucleotide polymorphisms such as dbSNP can be used as a reference. As to a probe used in the detection of a single nucleotide polymorphism, the detection can be made with either a probe complementary to a sense strand of the genome, or a probe complementary to an antisense strand. Although the details will be described later, a kit in which probes capable of detecting single nucleotide polymorphisms existing on the human genome are immobilized in large amounts, thereby making it possible to determine alleles of numerous single nucleotide polymorphisms in a single operation is commercially available, and whereby an allele in a sample can be efficiently determined using the kit. Many of the kits also have the constitution that the alleles that are opposite to each other contained in one sample are detected in a single operation, so that a genotype can be determined.

The single nucleotide polymorphism associated with glaucoma can be determined by previously identifying an allele existing on DNA from glaucoma patients and non-patients according to the method as mentioned above, statistically comparing each of the allele frequencies and the genotype frequencies in a glaucoma patient group against a non-patient group, and determining whether or not a difference that a p-value is below the significance level as defined by a given standard is caused in at least one of the allele frequencies and the genotype frequencies. In a case where the difference is caused, the allele frequencies or genotype frequencies for these factors in the glaucoma patient group and the non-patient group are compared to determine whether any of the alleles or genotypes are identified in a high frequency in the glaucoma patient group.

In the statistical analysis, for example, a chi-square test can be used. Type I error caused by multiple comparisons can be corrected by a known correction method, for example, Bonferroni method. In a case where a correction is based on Bonferroni correction, for example, a significance level can be obtained by dividing a p-value of 5×10⁻² by the number of multiple comparisons, i.e. the number of polymorphisms to be compared in the chi-square test. A single nucleotide polymorphism below the significance level determined in the manner described above can be selected as a more preferred single nucleotide polymorphism, and a method used in other known multiple corrections, for example, an FDR method or a permutation method may also be used in the selection of a preferred single nucleotide polymorphism. However, a known multiple correction method such as Bonferroni correction is a method presupposing that the phenomenon of carrying out multiple analyses is completely independent; on the other hand, there are some cases where the phenomenon is not completely independent because linkage disequilibrium is found in a single nucleotide polymorphism as described later. In other words, in the case as mentioned above, it is considered that overcorrection takes place when correction is carried out according to Bonferroni method. Especially, in the analysis of a single nucleotide polymorphism over the whole genome as in the present invention, factors to be statistically compared are highly enormous in number; therefore, a p-value serving as a standard is drastically lowered when multiple corrections are performed, so that a possibility of an oversight of a single nucleotide polymorphism associated with a disease becomes high (Schymick J C et al., Lancet Neurology. 2007: 6: 322-8; Van Steen K et al., Nature Genetics. 2005: 37: 683-691). An academically preferred multiple correction method is not yet established, and as other correction methods, correction by another known correction method can be carried out, or a significance level can be set at any appropriate levels within the range that would not be below the significance level according to the Bonferroni correction. When any appropriate level is set, for example, the significance level in a case where about 500,000 single nucleotide polymorphisms are analyzed repeatedly of 5×10⁻² is used, more preferably 1×10⁻², even more preferably 1×10⁻³, even more preferably 1×10⁻⁴, even more preferably 3×10⁻⁵, and even more preferably 1×10⁻⁵. As described later, the adjustment of the significance level as described above is useful from the fact that it is confirmed that a single nucleotide polymorphism identified to be associated with glaucoma in the present invention exists continuously in a certain region on the genome.

In addition, in general, it is known that type I error and the statistical power are inversely proportional. A method of maintaining the statistical power while lowering type I error includes a method of performing a single nucleotide polymorphism analysis in two divided steps (Skol A. D. et al., Nature Genetics. 2006: 38: 209-213). For example, in a case where a single nucleotide polymorphism analysis is carried out for a fixed number of samples, firstly, analysis of enormous single nucleotide polymorphisms over the whole genome for a part of samples thereof is carried out as primary analysis, and secondly, analysis of single nucleotide polymorphisms narrowed down in the first analysis to some degree is carried out for the remainder samples as secondary analysis. In this case, in both of the analyses, a single nucleotide polymorphism may be selected so as to have a relatively low p-value, for example, 0.05; preferably, a single nucleotide polymorphism serving as a candidate in the first analysis may be selected at a given significance level, and the selected single nucleotide polymorphism may be further analyzed using another sample. On the other hand, it is more preferable that the results of the first analysis and the secondary analysis are not individually statistically analyzed but these results are combined and analyzed. In the case as mentioned above, the two analytical results can be combined by a known method of meta-analysis, for example, Mantel-Haenszel method (Mantel N et al., Journal of the National Cancer Institute 1959: 22: 719-748). When the analytical results are combined according to a meta-analysis method such as Mantel-Haenszel method, the significance level for the selection of a single nucleotide polymorphism in individual analysis is not needed to be at the level of Bonferroni correction, and the significance level may be set by taking narrowing-down efficiency or the like into consideration. On the other hand, upon determination of whether or not a single nucleotide polymorphism is significant by a p-value combined by a meta-analysis method such as Mantel-Haenszel method, it is preferable to use a significance level with considering multiple comparisons. Here, the Mantel-Haenszel method refers to a method of combining analytical results by weighting the results obtained by multiple analyses when a chi-square test or the like is carried out. A statistical parameter combined by Mantel-Haenszel method includes, in addition to the p-value, an odds ratio described later or the like.

A single nucleotide polymorphism for the detection of the allele or genotype associated with glaucoma is preferably a single nucleotide polymorphism having a p-value of 1×10⁻³ or less, more preferably a single nucleotide polymorphism having a p-value of 3×10⁻⁴ or less, even more preferably a single nucleotide polymorphism having a p-value of 1×10⁻⁴ or less, and even more preferably a single nucleotide polymorphism having a p-value of 3×10⁻⁵ or less, when the single nucleotide polymorphism for the detection is based on the results obtained in a single analysis using, for example, a microarray in which about 500,000 single nucleotide polymorphisms are detected in a single operation. When the results are obtained by combining multiple analytical results according to a meta-analysis method such as Mantel-Haenszel method, the single nucleotide polymorphism for the detection is preferably a single nucleotide polymorphism having a p-value of 1×10⁻² or less, more preferably a single nucleotide polymorphism having a p-value of 3×10⁻³ or less, even more preferably a single nucleotide polymorphism having a p-value of 1×10⁻⁴ or less, and even more preferably a single nucleotide polymorphism having a p-value of 3×10⁻⁴ or less.

It is preferable that a sufficient number of single nucleotide polymorphisms are analyzed, in order to obtain highly reliable results upon analysis. For example, a polymorphic site having a low determination rate of each single nucleotide polymorphism to the whole sample, i.e. a low call rate, is likely to have a high rate of typing errors, so that the reliability is not high. Therefore, it is preferable that the analysis is performed using a single nucleotide polymorphism having a sufficiently high call rate. As to the call rate that serves as a standard of accepting or rejecting a single nucleotide polymorphism, for example, it is preferable that a single nucleotide polymorphism showing a call rate of preferably 70%, more preferably 75%, even more preferably 80%, even more preferably 85%, and even more preferably 90% or more is employed.

Besides them, factors that can be considered upon analysis are Hardy-Weinberg's equilibrium and minor allele frequency.

The Hardy-Weinberg's equilibrium means that a distribution frequency of the opposite alleles in a certain gene locus is constant even after generations, in a genetically homogeneous population having a sufficient number of individuals formed by panmixia without a mutation or selection pressure. Whether or not the Hardy-Weinberg's equilibrium is established can be confirmed by some known methods, for example, a chi-square test and a direct probability calculation method of Fischer. In a population of a sufficient number, it is considered that the Hardy-Weinberg's equilibrium is established by a single panmixia, i.e. the Hardy-Weinberg's equilibrium is established as long as inbreeding does not exist. Therefore, generally, under the assumption that the Hardy-Weinberg's equilibrium is established in the general population, analysis of the Hardy-Weinberg's equilibrium is used for the purpose of detecting errors of genotype determination of a sample. However, even if the Hardy-Weinberg's equilibrium is established as a whole, when a certain genotype is unevenly distributed in a disease group or a control group in a certain gene locus, for example, there are some cases where a certain genotype has a predominant influence on a disease, or the like; therefore, said analysis can be omitted, in a case where a search for disease-associated genes is carried out.

The minor allele frequency refers to an allele frequency with a lower frequency of the frequencies of two alleles in a case where single nucleotide polymorphisms are contained in two alleles. It is possible that a threshold thereof is arbitrarily set. As mentioned above, it is preferable that a single nucleotide polymorphism having a minor allele frequency of below 1% is rejected, because the concept of a single nucleotide polymorphism is in that the single nucleotide polymorphism has a minor allele frequency exceeding about 1%. On the other hand, there is a possibility that an allele having a very high or very low allele frequency in a disease group has a predominant influence on a disease. It is considered that polymorphisms of which relative involvement to a disease is relatively low are multiply involved in search of polymorphisms causative of multi-factorial diseases; therefore, for the purpose of searching the polymorphisms as mentioned above, an analysis excluding a frequency of a certain level or lower, for example, a minor allele of less than 5% can be a preferred means. On the other hand, in order to search polymorphisms that have predominant influences on a disease, it is effective not to reject the polymorphisms of the minor allele frequency.

From the allele or genotype associated with glaucoma thus obtained, the information such as a location on the genome at which a single nucleotide polymorphism exists, the sequence information, a gene in which a single nucleotide polymorphism exists or a gene existing in the neighborhood, discrimination of intron or exon or a function thereof in a case where the single nucleotide polymorphism exists on the gene, and a homologous gene in other organism species can be obtained, by referring to the database of known sequences such as GenBank, or the database of known single nucleotide polymorphisms such as dbSNP, whereby a nucleic acid molecule used in the present invention is obtained, on the basis of the information, and a probe or the like used in the present invention can be designed.

As the criteria for determining the presence or the absence of a risk in a single nucleotide polymorphism associated with glaucoma determined as mentioned above, a high-risk allele is defined. As mentioned above, in the present invention, the high-risk allele refers to an allele having a higher frequency in a glaucoma patient group than that of a non-patient group among each of the alleles of single nucleotide polymorphisms associated with glaucoma, and in the present invention, the low-risk allele refers to an allele opposite to a high-risk allele in a certain polymorphic site.

The determination of the presence or the absence of an onset risk can be carried out according to an allele or a genotype.

In a case where the determination is carried out according to an allele, the presence of the onset risk is determined for the single nucleotide polymorphism because of having a high-risk allele.

In a case where the determination is carried out according to a genotype, the onset risk is determined by taking into consideration whether the high-risk allele complies with a dominant genetic model, or with a recessive genetic model. In a certain polymorphic site, when the frequency of a homozygote of the high-risk allele and a heterozygote is significantly high in a glaucoma patient group as compared to that of a non-patient group, it is said that these genotypes comply with a dominant genetic model. The presence of an onset risk is determined for the single nucleotide polymorphism in a case where the genotype is a homozygote of the high-risk allele or a heterozygote, when the high-risk allele complies with a dominant genetic model. On the other hand, when the frequency of a homozygote of the high-risk allele is significantly high in a glaucoma patient group as compared to that of a non-patient group, it is said that these genotypes comply with a recessive genetic model. The presence of an onset risk is determined for the single nucleotide polymorphism in a case where the genotype is a homozygote of the high-risk allele, when the high-risk allele complies with a recessive genetic model.

The determination of the presence or the absence of an onset risk can be also carried out according to a low-risk allele. As mentioned above, the low-risk allele is an allele opposite to a high-risk allele, i.e. an allele identified in a high frequency in a non-patient group. In a case where the determination is carried out according to an allele, the presence of an onset risk is determined for the single nucleotide polymorphism because of not having a low-risk allele.

The same applies to a case of a genotype as well. When the determination is carried out according to a genotype, an onset risk is determined by taking into consideration whether the low-risk allele complies with a dominant genetic model, or with a recessive genetic model. In a certain polymorphic site, when the frequency of a homozygote of the low-risk allele and a heterozygote is significantly high in a non-patient group as compared to that of a glaucoma patient group, it is said that these genotypes comply with a dominant genetic model. The presence of an onset risk is determined for the single nucleotide polymorphism in a case where the genotype is not a homozygote of the low-risk allele or a heterozygote, when the low-risk allele complies with a dominant genetic model. On the other hand, when the frequency of a homozygote of the low-risk allele is significantly high in a non-patient group as compared to that of a glaucoma patient group, it is said that these genotypes comply with a recessive genetic model. The presence of an onset risk is determined for the single nucleotide polymorphism in a case where the genotype is not a homozygote of the low-risk allele, when the low-risk allele complies with a recessive genetic model.

As to whether the determination is carried out using a method for any of an allele, a dominant genetic model, and a recessive genetic model, the same method as in a method where a p-value judged to be significant is obtained can be used. In a case where the methods where a p-value judged to be significant is obtained exist in a plurality for one single nucleotide polymorphism, any of these methods may be used, and preferably, the same method as in a method where the lowest p-value is calculated is used.

Generally, in a single nucleotide polymorphism associated with a disease, a relative risk or an odds ratio is used as an index of an extent of the strength of the association that exists between one allele or genotype and the presence or the absence of a disease.

Generally, the relative risk refers to a ratio of an incidence rate in a group with a risk factor to an incidence rate in a group without a risk factor. On the other hand, the odds ratio generally refers to a ratio obtained by dividing odds, which is a ratio of a proportion of individuals with a risk factor to a proportion of individuals without a risk factor in a patient group, by odds obtained in a non-patient group in the same manner, which is in many cases used in a case-control study as in the present invention. The odds ratio in the present invention is determined on the basis of the allele frequency or the genotype frequency. In other words, the odds ratio of a single nucleotide polymorphism associated with the onset refers to a value obtained by calculating a quotient obtained in a ratio of an allele or genotype frequency to another allele or genotype frequency in a glaucoma patient group, over a ratio of frequencies obtained in the same manner in a non-patient group. In the present invention, an extent to which an onset risk of glaucoma increases can be predicted by comparing a case of having a certain allele or genotype to a case of having an allele or genotype other than the above, using these indices. For example, when an odds ratio of a certain allele in a certain single nucleotide polymorphism is greater than 1, the allele is an allele found in a high frequency in a glaucoma patient group, in which the larger the odds ratio, the higher the onset risk of glaucoma for a sample donor having the allele. On the other hand, when an odds ratio of an allele is less than 1, the allele is an opposite allele of the allele that is identified in a high frequency in a disease, in which the smaller the odds ratio, the lower the onset risk of glaucoma for a sample donor having the allele. The risk of a disease can also be predicted in the same manner for a genotype.

In the present invention, the value of the odds ratio would be always greater than 1 by obtaining an odds ratio based on the high-risk allele. The risk prediction in a combination of plural single nucleotide polymorphisms is facilitated by defining so that the odds ratio is greater than 1 when having the high-risk allele as mentioned above.

Although the details are shown by the numerical formulas in the section of Examples, in a case where an odds ratio is obtained for an allele, the odds ratio may be a value obtained by calculating a quotient obtained in a ratio of the high-risk allele frequency to the low-risk allele frequency in a glaucoma patient group, over a ratio of the high-risk allele frequency to the low-risk allele frequency in a non-patient group. In order to obtain an odds ratio in a genotype, the odds ratio is obtained by taking into consideration whether the high-risk allele complies with a dominant genetic model, or with a recessive genetic model. In other words, a homozygote of the high-risk allele and a heterozygote becomes a risk factor when the high-risk allele complies with a dominant genetic model, and a homozygote of the high-risk allele becomes a risk factor when the high-risk allele complies with a recessive genetic model. Therefore, when the high-risk allele complies with a dominant genetic model, the odds ratio may be obtained by obtaining the sum of the homozygote frequency of the high-risk allele and the heterozygote frequency in a glaucoma patient group, and calculating a quotient obtained in a ratio of the above sum to the homozygote frequency of the low-risk allele, over a ratio of frequencies obtained in the same manner in a non-patient group. When the high-risk allele complies with a recessive genetic model, the odds ratio may be obtained by obtaining the sum of the homozygote frequency of the low-risk allele and the heterozygote frequency in a glaucoma patient group, and calculating a quotient obtained in a ratio of the homozygote frequency of the high-risk allele to the above sum, over a ratio of frequencies obtained in the same manner in a non-patient group.

Further, the reliability of a single nucleotide polymorphism used in the prediction of a risk can be confirmed with an odds ratio. As mentioned above, the meaning for the prediction of a risk reverses in a case where the odds ratio is 1 or more and a case where the odds ratio is 1 or less. Therefore, in a case where a calculated 95% confidence interval of the odds ratio includes 1, it cannot be said that the reliability for the prediction of a risk for the odds ratio as mentioned above would be high.

In addition, in a case where an onset risk of glaucoma is predicted by a combination of single nucleotide polymorphisms of the present invention, the level of the risk can be predicted by using the level of the odds ratio.

In the odds ratio according to an allele, the odds ratio of combined two or more single nucleotide polymorphisms can be calculated according to the following formula:

(RA1_(comb)RA2_(comb))/(RA3_(comb)RA4_(comb))

wherein RA1_(comb): an allele frequency in a case where at least one allele is a high-risk allele in a glaucoma patient group; RA2_(comb): an allele frequency in a case where all the alleles are low-risk alleles in the glaucoma patient group; RA3_(comb): an allele frequency corresponding to RA1_(comb) in a non-patient group; and RA4_(comb): an allele frequency in a case where all the alleles are low-risk alleles in the non-patient group.

For example, in a case where two single nucleotide polymorphisms associated with the onset risk of glaucoma are combined, an odds is determined by dividing the frequencies in a glaucoma patient group all having high-risk alleles of a single nucleotide polymorphism, or having any one of high-risk alleles, by the frequency in the glaucoma patient group not having any one of high-risk alleles. The odds ratio in a case of a combination of the single nucleotide polymorphisms can be determined by calculating a ratio of said odds to the odds of that in a non-patient group obtained in the same manner.

In order to obtain an odds ratio according to a combination in cases of genotypes, the odds ratio is obtained by taking into consideration whether the high-risk allele complies with a dominant genetic model, or with a recessive genetic model, in the same manner as that alone.

In the odds ratio according to a dominant genetic model, the odds ratio of combined two or more single nucleotide polymorphisms can be calculated according to the following formula:

(RGd1_(comb)RGd2_(comb))/(RGd3_(comb)RGd4_(comb))

wherein RGd 1_(comb): a frequency at which at least one genotype is a homozygote of a high-risk allele or a heterozygote, in a glaucoma patient group; RGd2_(comb): a frequency at which all the genotypes are homozygotes of a low-risk allele in the glaucoma patient group; RGd3_(comb): a frequency of the genotype corresponding to RGd1_(comb) in a non-patient group; and RGd4_(comb): a frequency at which all the genotypes are homozygotes of a low-risk allele in the non-patient group.

For example, in a case where both the high-risk alleles of the two single nucleotide polymorphisms comply with a dominant genetic model, the odds ratio may be obtained by calculating a quotient obtained in a ratio of the frequency at which any of the two single nucleotide polymorphisms are a homozygote of a high-risk allele or a heterozygote in a glaucoma patient group to the frequency at which both the two single nucleotide polymorphisms are a homozygote of a low-risk allele in the glaucoma patient group, over a ratio of frequencies of those obtained in the same manner in a non-patient group.

In the odds ratio according to a recessive genetic model, the odds ratio of combined two or more single nucleotide polymorphisms can be calculated according to the following formula:

(RGr1_(comb)RGr2_(comb))/(RGr3_(comb)RGr4_(comb))

wherein RGr1_(comb): a frequency at which at least one genotype is a homozygote of a high-risk allele, in a glaucoma patient group; RGr2_(comb): a frequency at which all the genotypes are homozygotes of a low-risk allele in the glaucoma patient group; RGr3_(comb): a frequency of the genotype corresponding to RGr1_(comb) in a non-patient group; and RGr4_(comb): a frequency at which all the genotypes are homozygotes of a low-risk allele in the non-patient group.

For example, in a case where both the high-risk alleles of the two single nucleotide polymorphisms comply with a recessive genetic model, the odds ratio may be obtained by calculating a quotient obtained in a ratio of the frequency at which any of the two single nucleotide polymorphisms are a homozygote of a high-risk allele in a glaucoma patient group to the frequency at which both the two single nucleotide polymorphisms are a homozygote of a low-risk allele in the glaucoma patient group, over a ratio of frequencies of those obtained in the same manner in a non-patient group. Here, the odds ratio for a combination of single nucleotide polymorphisms can also be calculated by combining single nucleotide polymorphisms having different genetic forms.

Generally, the odds ratio increases by combining two or more single nucleotide polymorphisms, as compared to a case where these single nucleotide polymorphisms are used alone. Therefore, by a combination of two or more single nucleotide polymorphisms, a sample donor with a higher onset risk of glaucoma would be identified, whereby the improvement in the precision of the prediction can be made possible, as compared to the case where a single nucleotide polymorphism is used alone.

In order to confirm the improvement of the precision of the prediction of an onset risk of glaucoma according to a combination of single nucleotide polymorphisms in the present invention, a multivariate analysis can be employed. As the multivariate analysis method, a method well known to one of ordinary skill in the art such as logistic regression analysis method, discriminant analysis method, multiple linear regression analysis method, or proportional hazard analysis method can be employed, among which the logistic regression analysis method is effective in a case where a dichotomous variable such as the presence or the absence of an onset risk of glaucoma is handled.

The logistic regression analysis method refers to a method of analyzing a degree to which multiple independent variables (U) contribute in order to describe a single dependent variable (Φ) (Wakariyasui Igaku Tokeigaku (Easy Medical Statistics), pp. 148-179, Toshio MORIZANE, Medical Tribune). By performing the logistic regression analysis, a regression coefficient (λ) for each independent variable can be obtained, and this regression coefficient can be utilized as an index showing a degree to which each independent variable describes a dependent variable. In addition, a dependent variable on each obtained independent variable can be calculated by substituting this regression coefficient into the following formula:

Φ=1/{1+exp[−(λ0+λ1Π1+λ2Π2+λ3Π3+ . . . )]}

Here, when the logistic regression analysis is performed, the independent variables U used in analysis can be previously narrowed down using a stepwise method or the like. The stepwise method refers to a method for selecting independent variables Π so as to maximize the regression coefficients by adding an optional independent variable Π. In other words, it means that after the regression coefficient is maximized by adding an arbitrary independent variable Π, the same outcome is obtained even if another independent variable Π is further added.

In the present invention, by combining any two or more single nucleotide polymorphisms determined to be involved in the onset of glaucoma, the extent to which the precision of the prediction of an onset risk is improved can be known, as compared to that where each of the single nucleotide polymorphisms is used alone. Concretely, the above formula is obtained according to logistic regression analysis by using each of any two or more single nucleotide polymorphisms as an independent variable Π (homozygote of one allele=0, heterozygote=1, homozygote of an opposite allele=2). In each sample, a dependent variable Φ is calculated by substituting a variable for each single nucleotide polymorphism into this formula. When a dependent variable Φ is greater than a given threshold (for example, 0.5), this sample donor is determined to be a glaucoma patient. The determination results are collated with the matter of whether the sample donor having a single nucleotide polymorphism was actually the glaucoma patient. According to the combination of the two or more single nucleotide polymorphisms in the present invention, an improvement in a concordance proportion is confirmed, whereby the precision improvement by the combination can be confirmed.

In addition, the single nucleotide polymorphisms which exist in genetically sufficiently close locations to each other are inherited in linkage, not inherited independently, in some cases. In a certain population, a state in which a linkage as described above is held regardless of occurrence of a recombination by mating is referred to as a linkage disequilibrium, and a unit holding the linkage is referred to a haplotype block or an LD block.

In the experiment results by the present inventors, it is found that a single nucleotide polymorphism associated with glaucoma actually may exist in clusters in a relatively closely on the genome in some cases. It is considered that these regions belong to an LD block associated with glaucoma. In order to determine an LD block associated with glaucoma, the LD block can be determined by analyzing single nucleotide polymorphisms which exist in the region as many as possible by the method mentioned above, and applying an algorithm to determine an LD block, for example, an EM algorithm. In addition, when the single nucleotide polymorphism associated with glaucoma in the present invention belongs to a known LD block, the LD block can be considered as an LD block associated with glaucoma. Genome Browser provided on the interne web sites by California University at Santa Cruz, or the like can be consulted for a known LD block.

Because a single nucleotide polymorphism that belongs to an LD block associated with glaucoma is linked to a single nucleotide polymorphism associated with glaucoma identified according to the experiments of the present inventors, it can be considered that the single nucleotide polymorphism that belongs to an LD block associated with glaucoma also associates with glaucoma in the same manner; therefore, the single nucleotide polymorphism is used in the prediction of an onset risk or progressive risk of glaucoma. In addition, by re-determining a sequence within the LD block associated with glaucoma, or a sequence surrounding the single nucleotide polymorphism associated with glaucoma that is identified according to the experiments by the present inventors, there is a possibility that an unknown single nucleotide polymorphism which is linked with the single nucleotide polymorphism, in other words, which is associated with the onset of glaucoma or the progression thereof, is found. Whether or not the found single nucleotide polymorphism is actually associated with the onset of glaucoma or the progress thereof can be determined by comparing an allele or genotype frequency of a disease group with that of a control group in the same manner as explained above.

In the present invention, an intronic single nucleotide polymorphism (iSNP) refers to one in which a single nucleotide polymorphism is identified in intron. A coding single nucleotide polymorphism (cSNP) refers to one that is accompanied by a change in an amino acid sequence, such as a codon in which the single nucleotide polymorphism is mutated to a codon encoding other amino acids or a termination codon, among those in which single nucleotide polymorphisms exist in regions translated in a protein. A silent single nucleotide polymorphism (sSNP) refers to one without accompanying a change in an amino acid sequence, among those in which a single nucleotide polymorphism is identified in a coding region. A genomic single nucleotide polymorphism (gSNP) refers to one in which a single nucleotide polymorphism exists in a region not encoding the gene on the genome. A regulatory polymorphism (rSNP) refers to a single nucleotide polymorphism existing in a site that is thought to be involved in the transcriptional regulation.

As described above, a single nucleotide polymorphism may exist in any location on the genome, any cases of which can be associated with a disease. In a case where a single nucleotide polymorphism exists in the intron or a non-coding region, there may be some cases where the single nucleotide polymorphism may influence a gene expression control, or splicing that takes place after the gene transcription or stability of mRNA. In a case where a single nucleotide polymorphism exists in the coding region, by substitution of its base, a codon corresponding to a certain amino acid may be changed to a codon corresponding to a different amino acid, or may undergo a change, for example, a change to a termination codon, or the like, which may lead to a change in the structure of a protein encoded thereby. Changes in expression levels or functions of genes by these changes consequently lead to changes in expression levels or functions of proteins encoded by the genes, which can be causes for various diseases. In a case where the genomic single nucleotide polymorphism is associated with a disease, there is a possibility that a region including the polymorphic site is actually translated, and influences in some way to other gene expressions. In a case where a silent single nucleotide polymorphism is associated with a disease, it is considered that a different polymorphism associating with the disease exists in the surrounding of the single nucleotide polymorphism, and the polymorphism and the silent single nucleotide polymorphism are linked, so that the association with the disease is found. Similarly, in a single nucleotide polymorphism other than the silent single nucleotide polymorphism, even when the single nucleotide polymorphism itself is not a direct cause for glaucoma but links to a polymorphism which is the true cause for glaucoma existing in the surrounding, the association of these single nucleotide polymorphisms and glaucoma may be found in some cases. In the case as described above, as described later, a polymorphism which is causative of glaucoma can be found by re-sequencing the surrounding of the single nucleotide polymorphism in the present invention. However, in any case, these single nucleotide polymorphisms can be also used for the purpose of predicting an onset risk of glaucoma, regardless of whether or not these would be the true causes for the disease.

(Nucleic Acid Molecule Comprising Allele Associated with Glaucoma)

In an embodiment of the present invention, there are provided a nucleic acid molecule comprising a single nucleotide polymorphism associated with glaucoma, and a nucleic acid molecule having a sequence complementary to the nucleic acid molecule comprising a single nucleotide polymorphism associated with glaucoma.

The nucleic acid molecule comprising a single nucleotide polymorphism associated with glaucoma or the nucleic acid molecule having a sequence complementary to the nucleic acid molecule can be used as a marker for determining the level of the onset risk of glaucoma. Further, these nucleic acid molecules can be used as a probe for detecting an allele or an opposite allele thereof identified in a high frequency in glaucoma patients, or determining a genotype, in the single nucleotide polymorphism. In addition, in a case where the single nucleotide polymorphism exists on exon or in the neighborhood thereof, these nucleic acid molecules can be used in the detection of transcripts of genes.

The nucleic acid molecule constituting the genome of an eukaryote is constituted by double strands of a sense strand and an antisense strand complementary to the sense strand. In other words, the single nucleotide polymorphism also exists on the sense strand and the antisense strand, and the nucleic acid molecule of the present invention embraces both of these strands because the detection of a single nucleotide polymorphism of both the strands is equally significant.

Nucleic acid molecules comprising any one of single nucleotide polymorphisms listed in Tables 1 and 2, Tables 5 to 25, Tables 26 to 28 and Tables 29 to 51 shown later, nucleic acid molecules comprising any single nucleotide polymorphisms existing in a region or on a gene determined by the linkage disequilibrium data or the like listed in Tables 3 and 4 shown later, and nucleic acid molecules complementary to these nucleic acid molecules are all embraced in the nucleic acid molecule of the present invention.

In an embodiment of the present invention, the nucleic acid molecule of the present invention is preferably nucleic acid molecules comprising a single nucleotide polymorphism listed in Tables 1 and 2, Tables 26 to 28 or Tables 52 to 62 shown later, or nucleic acid molecules complementary thereto, wherein

in a case where the single nucleotide polymorphism is gSNP, the nucleic acid molecule is a nucleic acid molecule comprising a sequence from a next base of a known single nucleotide polymorphism on an upstream side of the sense strand to a base before a known single nucleotide polymorphism on a downstream side, or a nucleic acid molecule comprising a sequence complementary thereto,

in a case where the single nucleotide polymorphism is iSNP, sSNP or cSNP, the nucleic acid molecule is a nucleic acid molecule comprising a full length of the gene on the genome including the single nucleotide polymorphism, a nucleic acid molecule comprising a sequence complementary thereto, and a nucleic acid molecule containing a complementary DNA (cDNA) molecule comprising the single nucleotide polymorphism or a sequence complementary thereto,

in a case where the single nucleotide polymorphism is rSNP, the nucleic acid molecule is a nucleic acid molecule comprising a sequence from a next base of a known single nucleotide polymorphism on an upstream side of the sense strand to a full length of the gene existing downstream of a promoter region in which the single nucleotide polymorphism exists, or a nucleic acid molecule comprising a sequence complementary thereto.

The nucleic acid molecule in the present invention is not limited whether it is a deoxyribonucleic acid, a ribonucleic acid, or a peptide nucleic acid, and a nucleic acid molecule comprising a mixed sequence thereof is also embraced in the present invention. In a case where a ribonucleic acid is used in the nucleic acid molecule in the present invention, in the sequence of the nucleic acid molecule in the present invention (including a sequence complementary thereto), thymine may be read as uracil. In addition, these nucleic acid molecules may be subjected to chemical modifications as occasion demands, within the range that would not impair a function to be used in the present invention. In this case, the function refers to a function of accomplishing the purpose of using the nucleic acid molecule.

The nucleic acid molecule in the present invention can be synthesized by a known method, for example, a phosphoramidite method, on the basis of the sequence information disclosed herein, or the sequence information obtained by searching the information disclosed herein with the database. The nucleic acid molecule can be synthesized using a commercially available DNA synthesizer. In addition, the nucleic acid molecule in the present invention can be obtained from a sample comprising DNA from human according to a known method such as a PCR method, or in some nucleic acid molecules, can be obtained from a sample containing RNA from human according to a known method such as an RT-PCR method. As to primers that are necessary for the obtainment, one of ordinary skill in the art can design the primers on the basis of the sequence information disclosed herein, or the sequence information that can be searched from ID of the database disclosed herein. For example, in a case where a PCR method is used, primers having about 10 to about 30 bases that have sequences homologous to a part of the sequences of the nucleic acid molecule of interest can be used, and in a case where an RT-PCR method is used, the nucleic acid molecule can be obtained by carrying out reverse transcription reaction using an oligo dT primer, or a random hexamer, or the like to prepare cDNA, and amplifying a sequence of interest in the cDNA by the PCR method mentioned above.

The nucleic acid molecule has a length of preferably from 16 to 55 bases, and more preferably from 23 to 27 bases or 47 to 53 bases. It is preferable that the nucleic acid molecule is a nucleic acid molecule containing the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto.

When a nucleic acid molecule comprising a single nucleotide polymorphism associated with the onset of glaucoma is selected, in a case where the nucleic acid molecule is selected based on the results obtained in a single analysis using a microarray in which, for example, 500,000 nucleic acid molecules are detected in a single operation, the nucleic acid molecule in the present invention is preferably a nucleic acid molecule having a p-value of 1×10⁻³ or less, more preferably a nucleic acid molecule having a p-value of 3×10⁻⁴ or less, even more preferably a nucleic acid molecule having a p-value of 1×10⁻⁴ or less, and even more preferably a nucleic acid molecule having a p-value of 3×10⁻⁵ or less. In a case where plural analytic results are combined and obtained according to a method of meta-analysis, such as Mantel-Haenszel method, the nucleic acid molecule is preferably a nucleic acid molecule having a p-value of 1×10⁻² or less, more preferably a nucleic acid molecule having a p-value of 3×10⁻³ or less, even more preferably a nucleic acid molecule having a p-value of 1×10⁻³ or less, even more preferably a nucleic acid molecule having a p-value of 3×10⁴ or less, and even more preferably a nucleic acid molecule having a p-value of 1×10⁻⁴ or less.

As a different means of selecting a preferred nucleic acid molecule, a significance level is set according to a known multiple correction method, whereby a preferred nucleic acid molecule can be selected. In a case where a correction is based on Bonferroni correction, for example, a significance level can be obtained by dividing a p-value of 5×10⁻² by the number of multiple comparisons, i.e. the number of polymorphisms to be compared in the chi-square test. A nucleic acid molecule having a single nucleotide polymorphism below the significance level thus obtained may be selected as a more preferred nucleic acid molecule. Upon the selection, Bonferroni correction may be performed using a p-value that is combined according to a method of meta-analysis, such as Mantel-Haenszel method, and the number of single nucleotide polymorphisms to be subject for the meta-analysis. Other known methods used in multiple corrections, for example, an FDR method or a permutation method may be used in the selection of a preferred nucleic acid molecule.

(Method of Detecting Single Nucleotide Polymorphism Associated with Glaucoma and Method of Predicting Onset Risk of Glaucoma)

Another embodiment of the present invention provides a method of detecting the presence or absence of an allele or genotype having a high frequency in glaucoma patients in a sample containing a nucleic acid molecule from the genome. The samples may be any ones so long as the nucleic acid molecules from the genome can be extracted, and for example, blood, white blood cells, hair root, hair, saliva, oral mucosa cells, skin, tissues such as muscles or organs obtained by biopsy, or the like can be used.

As mentioned above, the nucleic acid molecule constituting the genome of an eukaryote is constituted by a sense strand and an antisense strand that are complementary to each other, and the determination of the allele of the single nucleotide polymorphism in the present invention can also be performed by detecting any one of the bases of the sense strand and the antisense strand of the polymorphic site.

As mentioned above, in the method of determining the presence or the absence of the allele or genotype in a sample containing a nucleic acid molecule, any means can be used. For example, hybridization is carried out using a probe specific to each of the alleles, preferably a probe in the present invention described later, which is designed based on the sequence information disclosed in the present invention, and each of the alleles can be detected by detecting signals therefor. In addition, each of the alleles opposite to each other, in other words, an allele having a high association to a disease for a certain single nucleotide polymorphism and an allele having a low association thereto are each provided with different labels, and a probe capable of hybridizing these alleles to a polymorphic site, or an immobilized probe such as a microarray in which each of alleles opposite to each other is immobilized is used, whereby each of the alleles opposite to each other contained in the same sample can be detected. In the constitution as described above, not only the alleles of the sample, but also the genotypes can be determined. In addition, in a case where an immobilized probe such as a microarray in which each of the alleles opposite to each other is immobilized on the same carrier is used, a constitution that the hybridization is carried out in a single operation, and that the detection is carried out in a single operation can be also taken.

As another method of detecting a single nucleotide polymorphism in the present invention, the following method can be utilized. Examples of a method of hybridization using a probe are Taqman method, Invader (registered trademark) method, LightCycler method, cyclin probe method, MPSS method, beads-array method, and the like, and any of these methods can be employed. As to the probe for detecting the same allele, a more preferred probe may differ in some cases depending upon a method used in the detection. The determination of the allele or genotype of the single nucleotide polymorphism in the present invention does not depend upon the detection method, and it is preferable to use a suitable probe depending upon the detection method.

The Taqman method is a method of detecting a genetic polymorphism using an oligoprobe having a given length in which a fluorescent substance is bound to a 5′-side, and a quencher is bound to a 3′-side. The presence or absence of the polymorphism is determined by hybridizing a probe to a nucleic acid molecule having a polymorphism of interest, cutting off a part of the probe on the 5′-side by a PCR reaction, and measuring a fluorescent amount emitted by a fluorescent substance.

The Invader method is a method of detecting a genetic polymorphism using a probe (reporter) which has a sequence common to a 3′-side of a nucleic acid molecule having a polymorphism, but the sequence on a 5′-side being completely different therefrom, and a probe (invader) having only a sequence common to a 5′-side. The nucleic acid molecules of interest and these two probes are hybridized, a product is then treated with a nuclease, a part of the cut-out reporter probe is hybridized with a probe for detection having a fluorescent substance and a quencher, a hybridization product is treated with a nuclease, and the fluorescent substance is released, whereby the presence or absence of the polymorphism is determined by a fluorescent amount thereof.

The LightCycler method is a method of detecting a polymorphism including the step of hybridizing a polymorphic detection probe having a fluorescent substance and an anchor probe having a quencher, to a nucleic acid molecule having a polymorphism previously amplified by PCR. If the hybridized DNA is gradually heated, the polymorphic detection probe is released when a given temperature is reached, and the presence or absence of the polymorphism is determined by measuring this fluorescent amount.

The cyclin probe method is a polymorphic analysis method utilizing a probe having a fluorescent substance or a quencher on each end of a DNA (DRD probe), wherein DNA sequences are bound in a manner that both ends of an RNA sequence having a sequence complementary to a polymorphic site of a nucleic acid molecule of interest are sandwiched. A DRD probe is hybridized to a nucleic acid molecule of interest previously amplified by PCR or the like, RNase is allowed to act on this complex, and a fluorescent dye is released, whereby the presence or absence of the polymorphism is determined by measuring this fluorescent amount.

The MPSS method is a method of performing polymorphic analysis using an encoded adaptor probe and a decoder probe. The encoded adaptor probe is an oligo DNA having a 4-bases long protruding end on a 5′-side, subsequently a recognition sequence for a restriction enzyme BbvI, and a single-stranded sequence bound to a decoder probe on a 3′-side. On the other hand, the decoder probe is a single-stranded oligo DNA having a fluorescent substance on a 3′-side, and the decoder probe containing 4 different sequences, each sequence specifically hybridizing to a single encoded adaptor probe. The nucleic acid molecule having a polymorphism is previously immobilized on beads, and an initiation adaptor containing a recognition sequence for BbvI is bound thereto, to digest with BbvI to form a 4-bases long protruding end. The ligation with the encoded adaptor probe is carried out sequentially from a 3′-side of the protruding 4 bases, and the sequence of the bound encoded adaptor is detected with a specified decoder probe.

The beads array method is a method of performing the determination of a genotype including the step of combining beads to which a probe for allele detection and an oligonucleotide (address sequence) specifying the location information on the array of signals detected by the probe for allele detection are bound. For example, there are Golden Gate Assay using beads immobilized with only an address sequence (23 bases) of Illumina, and Infinium (registered trademark) Assay using beads in which probes (50 bases) for allele detection are bound to an address sequence (30 bases). In both the methods, which location on an array the probes for allele detection are bound can be known for each of the beads arranged arbitrarily on the array, on the basis of the address sequence.

The method of the Golden Gate Assay will be shown hereinbelow. In the detection of a single nucleotide polymorphism, two kinds of probes (allele-specific probes) specifically hybridizing to each allele, and a probe capable of specifically hybridizing to a sequence located 1 to 20 bases downstream on the 3′-side of the single nucleotide polymorphism (downstream sequence recognition probe) are used. In the downstream sequence recognition probe, an address sequence for specifying the location on the array is provided. In addition, these three probes contain a sequence to which universal primers described later are bound. The three probes are annealed with a genomic DNA, and a DNA polymerase and a ligase are added thereto. By carrying out an extension reaction and a ligation reaction, an allele-specific product ligating a gap between the allele-specific probe and the downstream sequence recognition probe is formed. A reaction for PCR is carried out with this allele-specific product as a template using two kinds of fluorescent-labeled universal primers, each being specific to each allele, and a universal primer bound to the downstream sequence recognition probe. A labeled PCR product is hybridized to an oligonucleotide immobilized on beads via an address sequence. The fluorescence on the beads is detected with a confocal laser scanner, thereby determining an allele and a genotype.

The method of the Infinium Assay will be shown hereinbelow. An array by Illumina [Illumina, iSelect™ Genotyping BeadChip] described later is in accordance with this method. There are two methods in the detection of an allele by this array. In one method, two kinds of probes (probes for allele detection of 50 bases long, Infinium I type) only differing by a base at a 3′-end, wherein the 3′-end is a site for detecting a single nucleotide polymorphism, are used. Whole genome amplification for a genomic DNA is previously carried out, and fragmentation with an enzyme is carried out. The probe and the fragmented genomic DNA are hybridized, and thereafter an allele-specific extension reaction takes place, whereby a base on the downstream (3′-side) by a single base of a polymorphic site labeled with a single kind of a fluorescent dye is incorporated corresponding to the probe. In another method, one kind of probe without having an allele-specific sequence of a single nucleotide polymorphism in the probe is used (probe for allele detection of 50 bases, Infinium II type). A 3′-end of this probe has a sequence up to a single base upstream (5′-side) from a polymorphic site. The probe and the fragmented genomic DNA are hybridized, and according to a single base extension reaction, a base labeled with either one of two kinds of fluorescent dyes is incorporated corresponding to a single nucleotide polymorphic site of interest. In both the methods, the fluorescence is detected by a confocal laser scanner, thereby determining an allele and a genotype.

Here, the details of properties for length, modification and the like of probes used in the hybridization method mentioned above will be described later.

In addition, a method without carrying out hybridization with a probe includes PCR-RFLP method, SSCP method, mass spectrometry and direct sequencing method.

The PCR-RFLP method is a method including the steps of forming different DNA fragments according to enzymatic digestion of a nucleic acid molecule having a polymorphism due to the existence of a polymorphism in a cleavage site of the restriction enzyme in the nucleic acid molecule, and determining the presence or absence of a polymorphism from a difference in electrophoretic patterns thereof. A nucleic acid molecule of interest is amplified by PCR, this amplified fragment is cleaved with a restriction enzyme, and a fragment formed electrophoretically is analyzed. The length of the nucleic acid molecule comprising an amplified polymorphism is usually from 50 to 10,000 base pairs, and more preferably from 100 to 1,000 base pairs.

The SSCP method is a method including the steps of amplifying a nucleic acid molecule having a polymorphism by PCR, forming a single-stranded DNA, electrophoresing the product, and determining the presence or absence of a polymorphism from a difference in the electrophoretic patterns thereof. The nucleic acid molecule of interest is amplified by PCR, and a single-stranded DNA is formed by subjecting this amplified fragment to heat or an alkali treatment. This single-stranded DNA forms a base sequence-specific higher-order structure; therefore, if these amplified fragments are electrophoresed, a difference in the electrophoretic mobility is found due to the difference in its structure. The primer used in PCR is labeled with a radioisotope or fluorescent substance. In addition, the length of the nucleic acid molecule comprising an amplified polymorphism is usually from 50 to 10,000 base pairs, and more preferably from 100 to 1,000 base pairs.

The mass spectrometry is a method including the steps of ionizing a polymer with a matrix and a laser or the like, accelerating the ionized polymer in a high electric field to allow a flight to a detector, and identifying mass from a difference in the flight time, or the like. This mass spectrometry is combined with the above primer extension method or the like to detect a polymorphism. Concretely, a single base extension reaction is carried out with a primer complementary to a sequence up to a single base upstream of a polymorphic site of a nucleic acid molecule having a polymorphism, any one of 4 kinds of dideoxyribonucleotides, and deoxyribonucleic acids other than those corresponding the above, and a difference in mass of nucleic acid products having different sequences incorporated in a 3′-end is determined, whereby a polymorphism can be identified.

The direct sequencing method is a method of directly reading off a base sequence of a nucleic acid molecule having a polymorphism. Representative methods are called Sanger method (dideoxy method). A primer that is unlabeled or labeled with a radioisotope or a fluorescent substance is bound to a nucleic acid molecule of interest, an extension reaction with Klenow enzyme or the like is stopped with four kinds of dideoxyribonucleotides that are unlabeled or labeled with a radioisotope or a fluorescent substance, the product is digested with a restriction enzyme, and a DNA fragment generated is separated by electrophoresis. The base sequence of a 3′-end is read off in the order of fragments having a lower molecular weight on the basis of an electrophoretic image, thereby a base sequence containing a few bases before and after a polymorphism is determined. As a modified method thereof, there is a method called a primer extension method. This is a method including the steps of carrying out a single base extension reaction using a primer complementary to a sequence up to a single base upstream of a polymorphic site of a nucleic acid molecule having a polymorphism, and reading off any one of the sequences of the 4 kinds of dideoxyribonucleotides incorporated in the 3-end. There are various methods in the identification of this dideoxyribonucleotides; for example, 4 kinds of nucleotides are labeled with different fluorescent substances, and separated and identified electrophoretically. In addition, a method of converting pyrophosphoric acid formed during an extension reaction to ATP, and identifying its ATP from luminescence of luciferase is also employed. The length of the primer used in the extension reaction is usually from 10 to 300 base pairs, and preferably from 15 to 25 base pairs.

In the present invention, the hybridization means that a nucleic acid molecule having a certain sequence is associated with a nucleic acid molecule complementary to at least a part of the nucleic acid molecule via a hydrogen bond on the basis of base sequences that are complementary to each other. The kind of the complementary nucleic acid molecule associated with the original nucleic acid molecule may be identical or different, and a nucleic acid constituting these nucleic acid molecules can be a deoxyribonucleic acid, a ribonucleic acid, or a peptide nucleic acid. In these nucleic acid molecules, when referred to the ribonucleic acid, in the sequence of the nucleic acid molecule (including a complementary sequence), thymine may be read as uracil.

The stringent conditions in the present invention mean conditions in which a nucleic acid molecule having a sequence complementary to a partial sequence of a nucleic acid molecule having a certain sequence is specifically hybridized to the nucleic acid molecule (Fred M. Ausuble et al., Current Protocols in Molecular Biology, 2.10.1-2.10.16, John Wiley and Sons, Inc). Concrete examples of the conditions as described above include conditions such as a temperature lower than a melting temperature (Tm) of a complex formed between a nucleic acid molecule having a certain sequence and a complementary nucleic acid molecule hybridized to the nucleic acid molecule by preferably from about 5° to about 30° C., and by more preferably about 10° to about 25° C., a reaction solution for hybridization, such as SSC (mixed solution of sodium chloride and sodium citrate) in a concentration of 0.01 to 6-folds, SSPE (mixed solution of sodium chloride, sodium dihydrogenphosphate, and EDTA) or MES (a mixed solution of 2-(N-morpholino)ethanesulfonic acid and tetramethylammonium chloride) buffer, and hydrogen ion concentrations of a pH of from 6 to 8. For example, the stringent conditions in a case where an immobilized probe is prepared by immobilizing a 25 by DNA probe include conditions of hybridization at 49° C. in the MES buffer (hydrogen ion concentrations being from 6.5 to 6.7) in a 1-fold concentration, and sequentially washing with SSC (hydrogen ion concentrations being 8.0) in a 6-fold concentration at 25° C., and thereafter SSC (hydrogen ion concentrations being 8.0) in a 0.6-fold concentration at 45° C.

In the present invention, the term allele-specific (or specific to allele) means that the allele is contained in a sequence from the genome including the polymorphic site or in a prepared nucleic acid molecule including the polymorphic site, or a certain nucleic acid molecule is capable of specifically hybridizing under stringent conditions to a nucleic acid molecule having a sequence containing the allele in the polymorphic site, in other words, in the manner of being capable of discriminating the allele and the opposite allele.

Base sequences of 61 bases in length including a single nucleotide polymorphism associated with the onset of glaucoma, disclosed in the present invention, are composed of two pairs of base sequences which differ only by a base in the center (i.e. 31st base) (i.e. those pairs are consisting of a sequence having odd number of SEQ ID No. and a sequence having even number of SEQ ID No.), and the 31st base is a polymorphic site. The high-risk alleles in the polymorphic sites are listed in Tables 1 and 2 or Tables 52 to 63 given later. In any of these single nucleotide polymorphisms, in a case where the existence of an allele that exists in a high frequency in glaucoma patients is determined, a high-risk allele in a sample is detected, whereby the existence of the allele that exists in a high frequency in glaucoma patients can be determined.

In addition, as to any single nucleotide polymorphisms associated with the onset of glaucoma identified above, the genotype can be determined by detecting the presence or the absence of each of the alleles opposite to each other contained in one sample. In detail, in a case where only a certain allele is detected, the genotype is a homozygote of the allele, and in a case where two alleles are detected, the genotype is a heterozygote having the two alleles. In at least one of these single nucleotide polymorphisms, by detecting a genotype, it is determined whether or not the genotype that is identified in a higher frequency in a glaucoma patient group than that of a non-patient group exists in a sample. In other words, in the single nucleotide polymorphism mentioned above, when the high-risk allele complies with a dominant genetic model, a homozygote of the high-risk allele or a heterozygote is a genotype that is identified in a higher frequency in a glaucoma patient group than that of a non-patient group, and when the high-risk allele complies with a recessive genetic model, a homozygote of the high-risk allele is a genotype that is identified in a higher frequency in a glaucoma patient group than that of a non-patient group. It is preferable that each of the opposite alleles is measured in a single operation, from the viewpoint of reducing judgmental error.

The sample is analyzed in the manner described above, and in a case where the allele or genotype that is identified in a higher frequency in a glaucoma patient group than that of a non-patient group exists in the sample, there are some high probabilities that an individual donating the sample not having glaucoma at the present point is predicted to have a high onset risk of glaucoma, or is determined that a precision examination for glaucoma such as visual field examination is necessary, and that an individual donating the sample who is suspected of having glaucoma should be diagnosed as glaucoma.

In the method of detecting a single nucleotide polymorphism associated with glaucoma and the method of predicting an onset risk of glaucoma in the present invention, the single nucleotide polymorphism used in the detection is a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto,

more preferably a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto, even more preferably a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of pairs of base sequences containing a single nucleotide polymorphism listed below or a complementary sequence thereto, wherein, as mentioned above, in the pairs of SEQ ID NOs: shown in a to r, each of the pairs of sequences corresponds to one single nucleotide polymorphism, and each of the base sequences is a base sequence containing an allele opposite to each other of the single nucleotide polymorphism in a 31st base: a: SEQ ID NO: 203 and/or SEQ ID NO: 204, b: SEQ ID NO: 205 and/or SEQ ID NO: 206, c: SEQ ID NO: 207 and/or SEQ ID NO: 208, d: SEQ ID NO: 209 and/or SEQ ID NO: 210, e: SEQ ID NO: 211 and/or SEQ ID NO: 212, f: SEQ ID NO: 213 and/or SEQ ID NO: 214, g: SEQ ID NO: 215 and/or SEQ ID NO: 216, h: SEQ ID NO: 217 and/or SEQ ID NO: 218, i: SEQ ID NO: 219 and/or SEQ ID NO: 220, j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, l: SEQ ID NO: 225 and/or SEQ ID NO: 226, m: SEQ ID NO: 227 and/or SEQ ID NO: 228, n: SEQ ID NO: 229 and/or SEQ ID NO: 230, o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ. ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238.

In a case where any one of the single nucleotide polymorphisms is used, especially, it is preferable that an allele of a single nucleotide polymorphism located on a 31st base of a base sequence is used, wherein the base sequence is at least one base sequence selected from the group consisting of the following base sequences containing a single nucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 238, or a complementary sequence thereto. Here, these sequences are sequences containing a high-risk allele in each of polymorphic sites.

Further, the precision of the determination of a future onset risk of glaucoma can be improved by detecting a combination of two or more of alleles or genotypes associated with glaucoma in the present invention, using one sample.

For the single nucleotide polymorphisms to be combined, any ones can be used so long as they are a single nucleotide polymorphism in the present invention, preferably a single nucleotide polymorphism having a low p-value, and more preferably a single nucleotide polymorphism of which p-value obtained by combining the results obtained in two analyses by a meta-analysis method, such as Mantel-Haenszel method, is determined to be significant even below the level of Bonferroni correction. In addition, from a different viewpoint, it is preferable to use a single nucleotide polymorphism that is confirmed to contribute to the improvement in the precision of the risk prediction by a combination according to the logistic regression analysis described later. On the other hand, since the single nucleotide polymorphisms in a state of linkage disequilibrium mentioned above show the same behavior, in a case where plural single nucleotide polymorphisms in a state of linkage disequilibrium are combined, risks of glaucoma based on the same region may be evaluated unnecessarily seriously in some cases. In a case where a risk of a disease is predicted by combining the single nucleotide polymorphisms in the present invention, when it is intended to evaluate all the risks in even weighting, it is preferable that the prediction is carried out employing only one of the single nucleotide polymorphisms in the state of linkage disequilibrium, in a case that the plural single nucleotide polymorphisms that are in the state of linkage disequilibrium mentioned above are contained.

In a case where a risk is predicted according to a combination of any two or more single nucleotide polymorphisms in the present invention, an onset risk of glaucoma can be predicted using the regression formula obtained by the logistic regression analysis. Concretely, the regression formula according to the logistic regression analysis is obtained by respectively using each of the any two or more single nucleotide polymorphisms as an independent variable Π (homozygote of one allele=0, heterozygote=1, homozygote of an opposite allele=2). In each sample, a dependent variable Φ is calculated by substituting a value corresponding to each single nucleotide polymorphism into this formula. When a dependent variable Φ is greater than a given threshold (for example, 0.5), the determination can be made that this sample donor has an onset risk.

In the method of detecting a single nucleotide polymorphism associated with glaucoma and the method of predicting an onset risk of glaucoma in the present invention, in a case where any two or more single nucleotide polymorphisms are combined, the single nucleotide polymorphisms used in the detection are preferably single nucleotide polymorphisms which are located on 31st bases of base sequences, wherein the base sequences are base sequences containing two or more different single nucleotide polymorphisms, selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto,

more preferably single nucleotide polymorphisms which are located on 31st bases of base sequences, wherein the base sequences are base sequences containing two or more different single nucleotide polymorphisms, selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto, even more preferably single nucleotide polymorphisms which are located on 31st bases of base sequences, wherein the base sequences are base sequences containing two or more different single nucleotide polymorphisms, selected from the group consisting of pairs of base sequences containing a single nucleotide polymorphism listed below or a complementary sequence thereto, wherein, as mentioned above, in the pairs of SEQ ID NOs: shown in a to r, each of the pairs of sequences corresponds to one single nucleotide polymorphism, and each of the base sequences is a base sequence containing an allele opposite to each other of the single nucleotide polymorphism in a 31st base: a: SEQ ID NO: 203 and/or SEQ ID NO: 204, b: SEQ ID NO: 205 and/or SEQ ID NO: 206, c: SEQ ID NO: 207 and/or SEQ ID NO: 208, d: SEQ ID NO: 209 and/or SEQ ID NO: 210, e: SEQ ID NO: 211 and/or SEQ ID NO: 212, f: SEQ ID NO: 213 and/or SEQ ID NO: 214, g: SEQ ID NO: 215 and/or SEQ ID NO: 216, h: SEQ ID NO: 217 and/or SEQ ID NO: 218, i: SEQ ID NO: 219 and/or SEQ ID NO: 220, j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, l: SEQ ID NO: 225 and/or SEQ ID NO: 226, m: SEQ ID NO: 227 and/or SEQ ID NO: 228, n: SEQ ID NO: 229 and/or SEQ ID NO: 230, o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and even more preferably single nucleotide polymorphisms which are located on 31st bases of base sequences, wherein the base sequences are base sequences containing 10 or more different single nucleotide polymorphisms, selected from the group consisting of pairs of base sequences containing a single nucleotide polymorphism listed above or a complementary sequence thereto, and even more preferably single nucleotide polymorphisms which are located on 31st bases of base sequences, wherein the base sequences are base sequences containing all the different single nucleotide polymorphisms, selected from the group consisting of pairs of base sequences containing a single nucleotide polymorphism listed above or a complementary sequence thereto.

In addition, it is preferable that the single nucleotide polymorphisms to be used in combination are those that are not in the state of linkage disequilibrium, and from this viewpoint, in all the embodiments of the combinations mentioned above, supposing that

a group composed of a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: a: SEQ ID NO: 203 and/or SEQ ID NO: 204, and b: SEQ ID NO: 205 and/or SEQ ID NO: 206, or a complementary sequence thereto, is named as a single nucleotide polymorphism of Group 1, a group composed of a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: c: SEQ ID NO: 207 and/or SEQ ID NO: 208, and d: SEQ ID NO: 209 and/or SEQ ID NO: 210, or a complementary sequence thereto, is named as a single nucleotide polymorphism of Group 2, a group composed of a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, and l: SEQ ID NO: 225 and/or SEQ ID NO: 226, or a complementary sequence thereto, is named as a single nucleotide polymorphism of Group 3, a group composed of a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, or a complementary sequence thereto, is named as a single nucleotide polymorphism of Group 4, it is preferable to use any one of the single nucleotide polymorphisms in Group 1 in a case that the single nucleotide polymorphisms belonging to Group 1 are used, any one of the single nucleotide polymorphisms in Group 2 in a case that the single nucleotide polymorphisms belonging to Group 2 are used, any one of the single nucleotide polymorphisms in Group 3 in a case that the single nucleotide polymorphisms belonging to Group 3 are used, and/or any one of the single nucleotide polymorphisms in Group 4 in a case that the single nucleotide polymorphisms belonging to Group 4 are used.

Further, in all the embodiments of the combinations mentioned above, it is preferable that an allele of a single nucleotide polymorphism located on a 31st base of a base sequence is used, wherein the base sequence is a base sequence containing two or more different single nucleotide polymorphisms, selected from the group consisting of the following base sequences containing a single nucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 238, or a complementary sequence thereto. Here, these base sequences are sequences containing a high-risk allele in each of polymorphic sites.

(Probe Capable of Detecting Allele Associated with Glaucoma)

In another embodiment of the present invention, an allele-specific nucleic acid molecule or probe (hereinafter referred to as probe) capable of detecting an allele associated with glaucoma, and a method of detecting an allele or a genotype associated with glaucoma using the probe are provided.

Any probes may be used so long as the probe is capable of hybridizing under the stringent conditions to an allele-specific sequence, in a polymorphic site of the single nucleotide polymorphism associated with glaucoma in the present invention. The determination of the allele in a polymorphic site can be made by detecting any one of polymorphic sites of the sense strand and the antisense strand on the genome; therefore, the probe in the present invention embraces any one of sequences complementary to a sequence specific to an allele of the sense strand and sequences complementary to a sequence specific to an allele of the antisense strand, in other words, sequences specific to an allele of the sense strand. The probe in the present invention can also be used in the detection of cDNA or mRNA, containing a single nucleotide polymorphism in the present invention. In a case where the probe is used in the detection of cDNA or mRNA, a probe in which the single nucleotide polymorphism exists in exon or neighborhood thereof is used.

The probes capable of detecting each of alleles of the single nucleotide polymorphisms listed in Tables 1 and 2, Tables 5 to 25, Tables 26 to 28, Tables 29 to 51, or Tables 52 to 62 given later or a complementary strand thereto, and the probes capable of specifically detecting each of alleles of any single nucleotide polymorphisms that exist in a region associated with glaucoma listed in Tables 3 and 4 or Tables 63 to 70 given later or a complementary strand thereto are all embraced in the probe in the present invention. In a case where, for example, the obtained results are based on a single analysis using a microarray in which a probe capable of specifically detecting each of alleles of 500,000 single nucleotide polymorphisms, or a complementary strand thereto, is detected in a single operation, the probe of the present invention is preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 1×10⁻³ or less, more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 3×10⁻⁴ or less, even more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 1×10⁻⁴ or less, and even more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 3×10⁻⁵ or less. In a case where plural analytical results are combined and obtained according to a method of meta-analysis, such as Mantel-Haenszel method, the probe is preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 1×10⁻² or less, more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 3×10⁻³ or less, even more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 1×10⁻³ or less, even more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 3×10⁻⁴ or less, and even more preferably a probe capable of specifically detecting each of alleles of a single nucleotide polymorphism or a complementary strand thereto, of which p-value is 1×10⁻⁴ or less.

The probe in the present invention preferably contains an allele-specific sequence or a complementary strand thereto, and even more preferably in the probe in the present invention, a sequence contributing to an allele-specific hybridization consists only of an allele-specific sequence or a complementary strand thereto. To the probe in the present invention, a spacer or any sequences of several bases that are not from an allele-specific sequence for the purpose of providing stabilization or the like can be added in an end, within the range that the probe is capable of hybridizing to the sequence under the stringent conditions. The added sequence is preferably a sequence that does not take a three-dimensional structure, such as a hairpin structure.

The probe can be provided with any labels for use in the detection.

Any labels to be provided to the probe that are ordinarily used can be used, and in general, a fluorescent label such as FITC or Cy3, biotin, an enzyme label such as an alkaline phosphatase and horseradish peroxidase, or the like is usable. In a case where a biotin label is used, streptavidin capable of specifically binding to biotin is previously provided with a further detectable label, and the labeled streptavidin is used as a secondary label. A labeled anti-biotin antibody can also be used in place of the labeled streptavidin. As a method of providing a label to a probe, any known methods may be used, and the methods are well known to one of ordinary skill in the art. An arbitrary sequence which serves as a spacer as mentioned above may be added to the probe, and the spacer may be provided with a label. A reagent for labeling a probe, a labeled streptavidin, a labeled anti-biotin antibody or the like is commercially available as a reagent, and can also be purchased.

The probe in the present invention is not limited whether it is a deoxyribonucleic acid, a ribonucleic acid, or a peptide nucleic acid, and a probe containing a mixed sequence thereof is also embraced in the present invention, so long as the probe is capable of specifically hybridizing to a nucleic acid molecule having an allele of interest. In a case where a probe containing a ribonucleic acid is used as the probe in the present invention, in the sequence of the probe in the present invention (including a sequence complementary thereto), thymine may read as uracil. In addition, the probe in the present invention may be subjected to chemical modifications as needed, so long as the probe is capable of specifically hybridizing under stringent conditions to a nucleic acid molecule having an allele of interest. As the method of providing a chemical label, any known methods may be used.

The probe for the detection can be reacted with the sample in the state of solution and then detected by a known method, or previously immobilized to a carrier. The probe can take the form of an immobilized probe obtained by previously immobilizing a probe corresponding to each of the alleles of several to several hundred-thousand different single nucleotide polymorphisms to a location defined on a solid carrier in the number of from one to dozen probes per one single nucleotide polymorphism, reacting a sample to the immobilized probes, scanning a signal generated from a hybridized probe, and analyzing the scanned data with a computer, which is a so-called microarray. In a case where the probe takes the form of an immobilized probe, the largest number of the immobilized probes are limited by immobilization density and area of immobilized sites for the probes.

In a case where the probe takes the form of an immobilized probe as described above, signals on the solid phase from the nucleic acid molecule having a labeled target allele can be detected by previously labeling a nucleic acid molecule in a sample by a known method, and binding the labeled nucleic acid molecule with an immobilized unlabeled probe in the present invention, or by binding a nucleic acid molecule having an allele to be detected to an immobilized unlabeled probe in the present invention, and thereafter labeling the product according to a known method.

The immobilization can be carried out by any of known method, and for example, a method such as synthetic oligoprint or spotting photolithograph can be used. Also, the material for the carrier is not limited, and a generally used material, for example, a polymer such as a polycarbonate or a polystyrene, glass, silicon crystal or the like can be used. In addition, in order to enhance adhesive strength of the nucleic acids, a carrier may be provided with a coating such as cationization before the immobilization. In addition, in order to prevent nonspecific nucleic acids from being adsorbed to a carrier, blocking can be carried out with a known blocking agent after the immobilization. The blocking agent as mentioned above may be any ones so long as the blocking agent is capable of controlling the nonspecific nucleic acids from being adsorbed to the carrier, and for example, salmon sperm DNA, Denhardt's solution, Cot-I DNA extracted from human placenta, an anionic surfactant such as sodium dodecyl sulfate, a nonionic surfactant such as polyoxyethylene sorbitan monolaurate, or the like can be used.

In addition, in a case where the probe is immobilized, it is possible to construct that each of the opposite alleles contained in one sample is detected under the same operation by immobilizing a probe specific to each of the alleles opposite to each other on the same carrier. In the construction as described above, not only the alleles but also the genotypes in the samples can be determined.

It is preferable that the probe used in the detection of the allele is a probe having a length of preferably from 16 to 55 bases, more preferably from 23 to 27 bases or 47 to 53 bases, and even more preferably 25 bases in total of a length of the polymorphic site and some bases before and after the polymorphic site, the probe containing the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, that the probe is a probe containing the polymorphic site mentioned above and a 5′-upstream side thereof, preferably a sequence of 49 bases (i.e. a sequence of 50 bases), the probe containing the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, or that the probe is a probe containing a sequence of 50 bases on a 5′-upstream side of the polymorphic site mentioned above, the probe having a sequence adjoining the polymorphic site mentioned above, or a sequence complementary thereto.

An even more preferred probe used in the detection of the allele is:

1) a probe capable of specifically detecting an allele of the single nucleotide polymorphism, containing the polymorphic site mentioned above and a sequence of 12 bases each before and after the polymorphic site, i.e. a sequence of 25 bases in length, and the probe containing the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, or 2a) a probe capable of specifically detecting an allele of the single nucleotide polymorphism, containing the polymorphic site mentioned above and a sequence of 49 bases on the 5′-upstream side thereof (i.e. sequence of 50 bases), and the probe containing a sequence containing the polymorphic site mentioned above or a sequence complementary thereto, or 2b) a probe capable of specifically detecting an allele of the single nucleotide polymorphism, having a sequence of 50 bases on a 5′-upstream side of the polymorphic site mentioned above, and the probe having a sequence adjoining the polymorphic site mentioned above, or a sequence complementary thereto.

In the method of detecting a single nucleotide polymorphism associated with glaucoma and the method of predicting an onset risk of glaucoma in the present invention, the probe usable in the detection is a probe containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partial sequence thereof, and/or a probe having a base sequence containing at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto, more preferably a probe containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto, or a partial sequence thereof, and/or a probe having a base sequence containing at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 535 or a complementary sequence thereto, and

even more preferably a probe containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from following Group A consisting of pairs of base sequences a to r containing a single nucleotide polymorphism or a complementary sequence thereto, or a partial sequence thereof, and/or a probe containing a base sequence, wherein the base sequence is at least one base sequence or a pair of base sequences, selected from Group B consisting of base sequences aa to rr or pairs of the base sequences, or a complementary sequence thereto, wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs of sequences corresponds to one single nucleotide polymorphism, and each of the base sequences is a base sequence containing an allele opposite to each other of the single nucleotide polymorphism on a 31st base, and in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each of the base sequences or the pairs of the base sequences is a sequence for the probe or a pair of sequences for the probes, used in the detection of one single nucleotide polymorphism, wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff, g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and mm, n and nn, o and oo, p and pp, q and qq, and r and rr respectively correspond to the same single nucleotide polymorphism,

Group A

a: SEQ ID NO: 203 and/or SEQ ID NO: 204, b: SEQ ID NO: 205 and/or SEQ ID NO: 206, c: SEQ ID NO: 207 and/or SEQ ID NO: 208, d: SEQ ID NO: 209 and/or SEQ ID NO: 210, e: SEQ ID NO: 211 and/or SEQ ID NO: 212, f: SEQ ID NO: 213 and/or SEQ ID NO: 214, g: SEQ ID NO: 215 and/or SEQ ID NO: 216, h: SEQ ID NO: 217 and/or SEQ ID NO: 218, i: SEQ ID NO: 219 and/or SEQ ID NO: 220, j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, l: SEQ ID NO: 225 and/or SEQ ID NO: 226, m: SEQ ID NO: 227 and/or SEQ ID NO: 228, n: SEQ ID NO: 229 and/or SEQ ID NO: 230, o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,

bb: SEQ ID NO: 516, cc: SEQ ID NO: 517,

dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,

ee: SEQ ID NO: 519, ff: SEQ ID NO: 520, gg: SEQ ID NO: 521, hh: SEQ ID NO: 522, ii: SEQ ID NO: 523, jj: SEQ ID NO: 524, kk: SEQ ID NO: 525, ll: SEQ ID NO: 526, mm: SEQ ID NO: 527, nn: SEQ ID NO: 528, oo: SEQ ID NO: 529,

pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,

qq: SEQ ID NO: 531, and rr: SEQ ID NO: 532.

In a case where any one of the single nucleotide polymorphisms is used, especially, it is preferable that in Group A, a probe containing an allele of a single nucleotide polymorphism located on a 31st base of a base sequence is used, wherein the base sequence is at least one base sequence selected from the group consisting of the following base sequences containing a single nucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 238, or a complementary sequence thereto, or a partial sequence thereof, and in Group B, a probe containing a base sequence containing at least one base sequence selected from the group consisting of the following base sequences: SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO: 527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531, and SEQ ID NO: 532, or a complementary sequence thereto is used. Here, these base sequences are sequences corresponding to a probe used in the detection of a high-risk allele.

In the method of detecting a single nucleotide polymorphism associated with glaucoma and the method of predicting an onset risk of glaucoma in the present invention, in a case where any two or more single nucleotide polymorphisms are combined, the probes usable in the detection are preferably probes containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partial sequence thereof, and/or probes having a base sequence containing a base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto, wherein the probes are probes corresponding to two or more different single nucleotide polymorphisms thereof,

more preferably probes containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto, or a partial sequence thereof, and/or probes having a base sequence containing a base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 535 or a complementary sequence thereto, wherein the probes are probes corresponding to two or more different single nucleotide polymorphisms thereof, and even more preferably probes containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism selected from following Group A consisting of pairs of base sequences a to r containing a single nucleotide polymorphism or a complementary sequence thereto, or a partial sequence thereof, and/or two or more different probes having a base sequence, wherein the base sequence contains base sequences or a pair of base sequences, selected from Group B consisting of base sequences aa to rr or pairs of the base sequences, or a complementary sequence thereto, wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs of sequences corresponds to one single nucleotide polymorphism, and each of the base sequences is a base sequence containing an allele opposite to each other of the single nucleotide polymorphism on a 31st base, and in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each of the base sequences or the pairs of the base sequences is a sequence for the probe or a pair of sequences for the probes, used in the detection of one single nucleotide polymorphism, wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff, g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and mm, n and nn, o and oo, p and pp, q and qq, and r and rr respectively correspond to the same single nucleotide polymorphism,

Group A

a: SEQ ID NO: 203 and/or SEQ ID NO: 204, b: SEQ ID NO: 205 and/or SEQ ID NO: 206, c: SEQ ID NO: 207 and/or SEQ ID NO: 208, d: SEQ ID NO: 209 and/or SEQ ID NO: 210, e: SEQ ID NO: 211 and/or SEQ ID NO: 212, f: SEQ ID NO: 213 and/or SEQ ID NO: 214, g: SEQ ID NO: 215 and/or SEQ ID NO: 216, h: SEQ ID NO: 217 and/or SEQ ID NO: 218, i: SEQ ID NO: 219 and/or SEQ ID NO: 220, j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, l: SEQ ID NO: 225 and/or SEQ ID NO: 226, m: SEQ ID NO: 227 and/or SEQ ID NO: 228, n: SEQ ID NO: 229 and/or SEQ ID NO: 230, o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,

bb: SEQ ID NO: 516, cc: SEQ ID NO: 517,

dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,

ee: SEQ ID NO: 519, ff: SEQ ID NO: 520, gg: SEQ ID NO: 521, hh: SEQ ID NO: 522, ii: SEQ ID NO: 523, jj: SEQ ID NO: 524, kk: SEQ ID NO: 525, ll: SEQ ID NO: 526, mm: SEQ ID NO: 527, nn: SEQ ID NO: 528, oo: SEQ ID NO: 529,

pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,

qq: SEQ ID NO: 531, and rr: SEQ ID NO: 532,

even more preferably probes containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism selected from Group A listed above consisting of pairs of the base sequences containing the single nucleotide polymorphism or a complementary sequence thereto, or a partial sequence thereof, and/or probes having a base sequence, wherein the base sequence contains a base sequence selected from Group B listed above consisting of pairs of the base sequences or a complementary sequence thereto, wherein the probes are probes corresponding to 10 or more different single nucleotide polymorphisms thereof, and even more preferably probes containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism selected from Group A listed above consisting of pairs of the base sequences containing the single nucleotide polymorphism or a complementary sequence thereto, or a partial sequence thereof, and/or probes having a base sequence, wherein the base sequence contains a base sequence selected from Group B listed above consisting of pairs of the base sequences or a complementary sequence thereto, wherein the probes are probes corresponding to all the different single nucleotide polymorphisms thereof.

In addition, it is preferable that the single nucleotide polymorphisms to be used in combination are those that are not in the state of linkage disequilibrium, and from this viewpoint, in all the embodiments of the combinations mentioned above, supposing that, in Group A, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of:

a: SEQ ID NO: 203 and/or SEQ ID NO: 204, and b: SEQ ID NO: 205 and/or SEQ ID NO: 206, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 1, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: c: SEQ ID NO: 207 and/or SEQ ID NO: 208, and d: SEQ ID NO: 209 and/or SEQ ID NO: 210, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 2, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, and l: SEQ ID NO: 225 and/or SEQ ID NO: 226, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 3, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 4, and that in Group B, a group composed of a base sequence containing a base sequence belonging to the group consisting of: aa: SEQ ID NO: 515 and/or SEQ ID NO: 533, and

bb: SEQ ID NO: 516,

or a complementary sequence thereto, is named as a base sequence of Group 1, a group composed of a base sequence containing a base sequence belonging to the group consisting of:

cc: SEQ ID NO: 517, and

dd: SEQ ID NO: 518 and/or SEQ ID NO: 534 or a complementary sequence thereto, is named as a base sequence of Group 2, a group composed of a base sequence containing a base sequence belonging to the group consisting of:

jj: SEQ ID NO: 524, kk: SEQ ID NO: 525, and ll: SEQ ID NO: 526,

or a complementary sequence thereto, is named as a base sequence of Group 3, and a group composed of a base sequence containing a base sequence belonging to the group consisting of:

oo: SEQ ID NO: 529,

pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,

qq: SEQ ID NO: 531, and rr: SEQ ID NO: 532,

or a complementary sequence thereto, is named as a base sequence of Group 4, it is preferable to use a probe containing any one of the base sequences in Group 1 in a case that the base sequences belonging to Group 1 are used, a probe containing any one of the base sequences in Group 2 in a case that the base sequences belonging to Group 2 are used, a probe containing any one of the base sequences in Group 3 in a case that the base sequences belonging to Group 3 are used, and/or a probe containing any one of the base sequences in Group 4 in a case that the base sequences belonging to Group 4 are used.

Further, in all the embodiment of the combinations mentioned above, in Group A, a probe containing an allele of a single nucleotide polymorphism located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism selected from the group consisting of the following base sequences containing a single nucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 238, or a complementary sequence thereto, or a partial sequence thereof, is preferred, and in Group B, a probe containing a base sequence containing a base sequence selected from the group consisting of the following base sequences: SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO: 527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531, and SEQ ID NO: 532, or a complementary sequence thereto is preferred. Here, these base sequences are sequences corresponding to a probe used in the detection of a high-risk allele.

The probe in a case where a Taqman method is used in the detection of an allele usually has a length of preferably from 10 to 300 bases, and contains the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, and the probe also contains a fluorescent substance and a quencher. More preferably, the probe has a length of 20 to 60 bases, and contains the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, and the probe contains a fluorescent substance and a quencher.

The probes in a case where an Invader method is used in the detection of an allele comprise a probe (reporter) which have a common sequence to a 3′-side of the polymorphic site mentioned above and a sequence on a 5′-side being completely different therefrom, and a probe (invader) only composed of the common sequence to a 5′-side. These probes usually have a length of preferably from 10 to 300 bases, and more preferably a length of from 20 to 60 bases.

The probe in a case where a LightCycler method is used in the detection of an allele, usually has a length of preferably from 10 to 300 bases, and contains the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, and the probe contains a fluorescent substance and a quencher. More preferably, the probe has a length of 20 to 60 bases, and contains the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, and the probe contains a fluorescent substance and a quencher.

The probe in a case where a cyclin probe method is used in the detection of an allele is a probe in which DNA sequences are bound in a manner that both ends of an RNA sequence having the polymorphic site and a surrounding sequence thereof, or a sequence complementary thereto, are sandwiched, and each of DNA ends has a fluorescent substance or a quencher. These probes usually have a length of preferably from 10 to 300 bases, and contain the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto. More preferably, the probe has a length of 20 to 60 bases, and contains the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto.

The probes in a case where an MPSS method is used in the detection of an allele comprise an oligo DNA (encoded adaptor probe) having a protruding end of 4 bases on a 5′-side, subsequently a recognition sequence for a restriction enzyme BbvI, and a single-stranded sequence to which a decoder probe is bound on a 3′-side, and a single strand oligo DNA (decoder probe) which has fluorescent substance on a 3′-side, and containing 4 different sequences, each sequence specifically hybridizing to one of the encoded adaptor probes. Here, a DNA sequence is bound in a manner that both ends of an RNA sequence having the polymorphic site mentioned above and a surrounding sequence thereof, or a sequence complementary thereto, are sandwiched, and each of DNA ends has a fluorescent substance or a quencher. The encoded adaptor probe usually has a length of preferably from 10 to 300 base pairs, and more preferably from 15 to 40 base pairs. On the other hand, the decoder probe usually has a length of preferably from 10 to 300 base pairs, and more preferably from 5 to 30 base pairs.

(Kit of Detecting Allele Associated with Glaucoma)

In another embodiment of the present invention, a kit of detecting a single nucleotide polymorphism associated with glaucoma is provided.

The kit of the present invention (or a composition for predicting a risk) embraces all those kits so long as the allele or genotype of any one of single nucleotide polymorphisms associated with glaucoma disclosed in the present invention can be detected in a nucleic acid molecule in a sample. As mentioned above, the kit of the present invention may be those that detect a base of either the sense strand or the antisense strand of the single nucleotide polymorphism, or those that detect bases of both the strands. In a case where the kit of the present invention is based on the results obtained in a single analysis using a microarray for a kit of detecting an allele or genotype associated with glaucoma for detecting, for example, 500,000 single nucleotide polymorphisms in a single operation, the kit is preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 1×10⁻⁴ or less listed in Tables 1 and 2 set forth below, more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 3×10⁴ or less, even more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 1×10⁻⁴ or less, and even more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 3×10⁻⁵ or less. In a case where the plural analytic results are combined and obtained according to a method of meta-analysis, such as Mantel-Haenszel method, the kit is preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value listed in Tables 52 to B set forth below of 1×10⁻² or less, more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 3×10⁻³ or less, even more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 1×10⁻³ or less, even more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 3×10⁻⁴ or less, and even more preferably a kit of detecting an allele or genotype associated with glaucoma for single nucleotide polymorphisms having a p-value of 1×10⁻⁴ or less.

A kit of detecting both an allele identified in a high frequency in the glaucoma patient group mentioned above and an allele opposite to the allele is also one embodiment of the present invention. In a case where a kit as described above is used, as already explained, a genotype of each of the alleles can also be determined.

By detecting the presence of an allele or a genotype that is identified in a high frequency in glaucoma patients in the sample using the kit of the present invention, a future onset risk of glaucoma of an individual not having glaucoma at the present stage can be predicted, whether or not precise visual field examinations for glaucoma are required can be determined, or the diagnosis of an individual who is suspected of glaucoma can be made for glaucoma.

In addition, as mentioned above, a kit for determining alleles that are opposite to each other in a single operation can be prepared by using a probe specific to each of the alleles that are opposite to each other, and providing different labels to the probes, or providing in the form of a microarray or beads array as mentioned above.

The precision for the prediction of the onset risk of glaucoma or the determination of whether or not precise visual field examinations are required can also be improved by providing a kit having the constitution of detecting these plural alleles or genotypes using one sample. Even in the constitution as described above, a constitution can be taken that the detection is carried out in a single operation by having the form of probes provided with different labels, or the form of the microarray or beads array mentioned above.

In the method of detecting a single nucleotide polymorphism associated with glaucoma and the method of predicting an onset risk of glaucoma in the present invention, the kit usable in detecting or predicting a risk is

a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto, more preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 535 or a complementary sequence thereto, even more preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from following Group A consisting of pairs of base sequences a to r containing a single nucleotide polymorphism or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing at least one base sequence or a pair of base sequences, selected from Group B consisting of base sequences aa to rr or pairs of the base sequences, or a complementary sequence thereto, wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs of sequences corresponds to one single nucleotide polymorphism, and each of the base sequences is a base sequence containing an allele opposite to each other of the single nucleotide polymorphism on a 31st base, and in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each of the base sequences or the pairs of the base sequences is a sequence for the nucleic acid molecule or a pair of sequences for the nucleic acid molecule, used in the detection of one single nucleotide polymorphism, wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff, g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and mm, n and nn, o and oo, p and pp, q and qq, and r and rr respectively correspond to the same single nucleotide polymorphism,

Group A

a: SEQ ID NO: 203 and/or SEQ ID NO: 204, b: SEQ ID NO: 205 and/or SEQ ID NO: 206, c: SEQ ID NO: 207 and/or SEQ ID NO: 208, d: SEQ ID NO: 209 and/or SEQ ID NO: 210, e: SEQ ID NO: 211 and/or SEQ ID NO: 212, f: SEQ ID NO: 213 and/or SEQ ID NO: 214, g: SEQ ID NO: 215 and/or SEQ ID NO: 216, h: SEQ ID NO: 217 and/or SEQ ID NO: 218, i: SEQ ID NO: 219 and/or SEQ ID NO: 220, j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, l: SEQ ID NO: 225 and/or SEQ ID NO: 226, m: SEQ ID NO: 227 and/or SEQ ID NO: 228, n: SEQ ID NO: 229 and/or SEQ ID NO: 230, o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,

bb: SEQ ID NO: 516, cc: SEQ ID NO: 517,

dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,

ee: SEQ ID NO: 519, ff: SEQ ID NO: 520, gg: SEQ ID NO: 521, hh: SEQ ID NO: 522, ii: SEQ ID NO: 523, jj: SEQ ID NO: 524, kk: SEQ ID NO: 525, ll: SEQ ID NO: 526, mm: SEQ ID NO: 527, nn: SEQ ID NO: 528, oo: SEQ ID NO: 529,

pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,

qq: SEQ ID NO: 531, and rr: SEQ ID NO: 532.

In a case where any one of the single nucleotide polymorphisms is used, especially, in Group A, preferred is a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or predicting an onset risk of glaucoma, using a nucleic acid molecule containing an allele of a single nucleotide polymorphism located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of the following base sequences containing a single nucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 238, or a complementary sequence thereto, or a partial sequence thereof, and in Group B, preferred is a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing a base sequence selected from the group consisting of the following base sequences: SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO: 527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531, and SEQ ID NO: 532, or a complementary sequence thereto. Here, these base sequences are sequences corresponding to a nucleic acid molecule used in the detection of a high-risk allele.

In the method of detecting a single nucleotide polymorphism associated with glaucoma and the method of predicting an onset risk of glaucoma in the present invention, in a case where any two or more single nucleotide polymorphisms are combined, the kit usable in detecting or predicting a risk is

preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing a base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto, wherein the kit is a kit corresponding to two or more different single nucleotide polymorphisms thereof, more preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 218 or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing a base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 515 to 535 or a complementary sequence thereto, wherein the kit is a kit corresponding to two or more different single nucleotide polymorphisms thereof, even more preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from the group consisting of the following pairs of base sequences containing a single nucleotide polymorphism or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence, wherein the base sequence contains a base sequence or a pair of base sequences, selected from Group B consisting of base sequences aa to rr or pairs of the base sequences, or a complementary sequence thereto, wherein the kit is a kit corresponding to two or more different single nucleotide polymorphisms thereof, wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs of sequences corresponds to one single nucleotide polymorphism, and each of the base sequences is a base sequence containing an allele opposite to each other of the single nucleotide polymorphism on a 31st base, and in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each of the base sequences or the pair of base sequences is a sequence for the nucleic acid molecule or a pair of sequences for the nucleic acid molecule, used in the detection of one single nucleotide polymorphism, wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff, g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and mm, n and nn, o and oo, p and pp, q and qq, and r and rr respectively correspond to the same single nucleotide polymorphism,

Group A

a: SEQ ID NO: 203 and/or SEQ ID NO: 204, b: SEQ ID NO: 205 and/or SEQ ID NO: 206, c: SEQ ID NO: 207 and/or SEQ ID NO: 208, d: SEQ ID NO: 209 and/or SEQ ID NO: 210, e: SEQ ID NO: 211 and/or SEQ ID NO: 212, f: SEQ ID NO: 213 and/or SEQ ID NO: 214, g: SEQ ID NO: 215 and/or SEQ ID NO: 216, h: SEQ ID NO: 217 and/or SEQ ID NO: 218, i: SEQ ID NO: 219 and/or SEQ ID NO: 220, j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, l: SEQ ID NO: 225 and/or SEQ ID NO: 226, m: SEQ ID NO: 227 and/or SEQ ID NO: 228, n: SEQ ID NO: 229 and/or SEQ ID NO: 230, o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,

bb: SEQ ID NO: 516, cc: SEQ ID NO: 517,

dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,

ee: SEQ ID NO: 519, ff: SEQ ID NO: 520, gg: SEQ ID NO: 521, hh: SEQ ID NO: 522, ii: SEQ ID NO: 523, jj: SEQ ID NO: 524, kk: SEQ ID NO: 525, ll: SEQ ID NO: 526, mm: SEQ ID NO: 527, nn: SEQ ID NO: 528, oo: SEQ ID NO: 529,

pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,

qq: SEQ ID NO: 531, and rr: SEQ ID NO: 532,

even more preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from Group A consisting of pairs of the base sequences containing a single nucleotide polymorphism listed above or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing a base sequence selected from Group B consisting of pairs of the base sequences listed above or a complementary sequence thereto, wherein the kit is a kit corresponding to ten or more different single nucleotide polymorphisms thereof, and even more preferably a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from Group A consisting of pairs of the base sequences containing a single nucleotide polymorphism listed above or a complementary sequence thereto, or a partial sequence thereof, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing a base sequence selected from Group B consisting of pairs of the base sequences listed above or a complementary sequence thereto, wherein the kit is a kit corresponding to all the different single nucleotide polymorphisms thereof.

In addition, it is preferable that the single nucleotide polymorphisms to be used in combination are those that are not in the state of linkage disequilibrium, and from this viewpoint, in all the embodiments of the combinations mentioned above, supposing that, in Group A, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of:

a: SEQ ID NO: 203 and/or SEQ ID NO: 204, and b: SEQ ID NO: 205 and/or SEQ ID NO: 206, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 1, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: c: SEQ ID NO: 207 and/or SEQ ID NO: 208, and d: SEQ ID NO: 209 and/or SEQ ID NO: 210, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 2, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: j: SEQ ID NO: 221 and/or SEQ ID NO: 222, k: SEQ ID NO: 223 and/or SEQ ID NO: 224, and l: SEQ ID NO: 225 and/or SEQ ID NO: 226, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 3, a group composed of a base sequence containing a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is a base sequence belonging to the group consisting of: o: SEQ ID NO: 231 and/or SEQ ID NO: 232, p: SEQ ID NO: 233 and/or SEQ ID NO: 234, q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and r: SEQ ID NO: 237 and/or SEQ ID NO: 238, or a complementary sequence thereto, or a partial sequence thereof, is named as a base sequence of Group 4, and that in Group B, a group composed of a base sequence containing a base sequence belonging to the group consisting of: aa: SEQ ID NO: 515 and/or SEQ ID NO: 533, and

bb: SEQ ID NO: 516,

or a complementary sequence thereto, is named as a base sequence of Group 1, a group composed of a base sequence containing a base sequence belonging to the group consisting of:

cc: SEQ ID NO: 517, and

dd: SEQ ID NO: 518 and/or SEQ ID NO: 534 or a complementary sequence thereto, is named as a base sequence of Group 2, a group composed of a base sequence containing a base sequence belonging to the group consisting of:

jj: SEQ ID NO: 524, kk: SEQ ID NO: 525, and ll: SEQ ID NO: 526,

or a complementary sequence thereto, is named as a base sequence of Group 3, and a group composed of a base sequence containing a base sequence belonging to the group consisting of:

oo: SEQ ID NO: 529,

pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,

qq: SEQ ID NO: 531, and rr: SEQ ID NO: 532,

or a complementary sequence thereto, is named as a base sequence of Group 4, it is preferable to use a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising any one of the base sequences in Group 1 when the base sequences belonging to Group 1 are used, a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising any one of the base sequences in Group 2 when the base sequences belonging to Group 2 are used, a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising any one of the base sequences in Group 3 when the base sequences belonging to Group 3 are used, and/or a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising any one of the base sequences in Group 4 when the base sequences belonging to Group 4 are used.

In all the combinations mentioned above, in Group A, preferred is a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising an allele of a single nucleotide polymorphism located on a 31st base of a base sequence, wherein the base sequence is a base sequence containing a single nucleotide polymorphism, selected from the group consisting of the following base sequences containing a single nucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO: 238, or a complementary sequence thereto, or a partial sequence thereof, and in Group B, preferred is a kit of detecting a single nucleotide polymorphism associated with the onset of glaucoma or a kit of predicting an onset risk of glaucoma, using a nucleic acid molecule comprising a base sequence containing a base sequence selected from the group consisting of the following base sequences: SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO: 527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531, and SEQ ID NO: 532, or a complementary sequence thereto. Here, these base sequences are sequences corresponding to a nucleic acid molecule used in the detection of a high-risk allele.

(Method of Predicting Onset Risk of Glaucoma, Including Performing the Predicting Risk in Two-Steps or Multi-Steps)

When a prediction of an onset risk of glaucoma using a single nucleotide polymorphism in the present invention is carried out, it can be performed in two or more steps as follows; candidates who are considered that precise prediction of an onset risk of glaucoma is necessary are selected, and the candidates are subjected to detailed prediction of a risk.

In a case where prediction of a risk is performed in two or more multi-steps, first, prediction of an onset risk of glaucoma mentioned above is preformed on at least one single nucleotide polymorphism in the present invention, preferably any one or several single nucleotide polymorphisms, and subsequently, prediction of detailed risks may be performed using a combination of the single nucleotide polymorphisms of the present invention mentioned above. The number of combinations may be further increased as occasion demands, whereby precision of the prediction of a risk can also be improved. As described above, by performing prediction of a risk in two or more multi-steps, the reduction in costs for performing the prediction of a risk and the prediction of a risk in a high precision can be both accomplished.

The prediction of a risk in an initial step may be a convenient method of predicting a risk. For example, a method of predicting a risk so that an immobilized probe capable of detecting at least one of the single nucleotide polymorphisms, preferably any one or several single nucleotide polymorphisms, is immobilized in a manner that at least one of the single nucleotide polymorphisms in the present invention is detectable is a convenient method, and can be realized at a low cost. Here, as to a method for nucleic acid extraction in this case, a kit that can be realized according to a known technique, or a commercially available simple kit for nucleic acid extraction can be used. It is convenient to use a method including the steps of using, for example, an enzyme-labeled probe as the immobilized probe used in the prediction of a risk as described above, and detecting the probe according to a colorimetric method. As to the samples used in the detection, those that are obtained in a relatively low penetration, such as saliva, oral mucosa cells, urine, hair root, blood or white blood cells are preferred.

The prediction of a risk in a next step may be a method of predicting a risk with an emphasis on precision. For example, the detection of a single nucleotide polymorphism associated with the onset of glaucoma is carried out by combining two or more single nucleotide polymorphisms in the present invention mentioned above, whereby prediction of a risk may be performed in a high precision.

By performing prediction of a risk in two or more multi-steps, the precision for prediction of a risk can be improved, while reducing the costs or lowering a burden on a subject at an initial step to a minimum level.

According to the method disclosed in the present invention, the determination can be made that an individual who has an allele or genotype on the genome that is identified in a high frequency in glaucoma patients disclosed in the present invention has a high risk of the onset of glaucoma in future, and that an individual who does not have an allele or genotype that is identified in a high frequency in the glaucoma patients has a low risk of the onset of glaucoma in future.

In addition, an individual having an allele or genotype on the genome that is identified in a high frequency in glaucoma patients disclosed in the present invention has a possibility of being in an early stage of glaucoma that is difficult to be diagnosed according to a simple method of determination of glaucoma, such as measurement of intraocular pressure or examination of ocular fundus, and that is diagnosed for the first time after performing visual field examination. Therefore, a single nucleotide polymorphism in the present invention is detected, whereby whether or not the visual field examination is required can be screened. On the other hand, in a case where an individual who is suspected of being glaucoma has an allele or genotype associated with glaucoma in the present invention on the genome, there is a high probability that the individual who is suspected of being glaucoma is to be diagnosed as glaucoma.

EXAMPLES

The present invention will be specifically described hereinbelow by Examples, and Examples are given for illustration purposes for a better comprehension of the present invention, without intending to limit the scope of the present invention thereto. Here, in the following Examples, as to generally used molecular biological methods that are not specifically described in detail, methods and conditions described in a textbook such as Molecular Cloning (Joseph Sambrook et al., Molexular Cloning—A Laboratory Manual, 3rd Edition, Cold Spring Harbor Laboratory Press, 2001) or the like are used.

In the present invention, a total DNA was extracted from blood of each of patients diagnosed as glaucoma, and non-patients diagnosed as being not with glaucoma and determined not to have any family history in glaucoma according to a medical interview, and gene loci associated with the disease were analyzed based on about 500,000 known single nucleotide polymorphisms on the human genome as an index to determine an association of a single nucleotide polymorphism and the disease. In addition, patients with fast progression of glaucoma, i.e. progressive glaucoma cases, and patients with slow progression of glaucoma, i.e. nonprogressive glaucoma cases were subjected to the identification of a single nucleotide polymorphism and the association of the single nucleotide polymorphism with the progression in the same manner as above.

Example 1 DNA Extraction from Specimens

In DNA extraction from specimens, a commercially available automated nucleic acid extraction apparatus (QUIAGEN, BIOROBOT (registered trademark) EZ1), and a kit for extraction of a nucleic acid (EZ1 DNA Blood 350 μl Kit) compatible to the extraction apparatus and in which nucleic acids absorbed to magnetic beads were collected by a magnetic force were used. A total DNA was extracted in accordance with the instruction manuals of the apparatus and kit. According to the present method, a total DNA of about 5 μg was obtained from 350 μL of a blood specimen.

Example 2 Analysis of Single Nucleotide Polymorphism

In the analysis of single nucleotide polymorphisms, a commercially available microarray type single nucleotide polymorphism analysis kit (Affimetrix (GeneChip(registered trademark) Human Mapping 500K) (hereinafter also referred to as microarray) capable of analyzing about 500,000 known single nucleotide polymorphisms on the human genome was used. In the detection of single nucleotide polymorphisms, a scanner (Affimetrix (GeneChip(registered trademark) Scanner 3000)) compatible to the kit was used. In the analysis of single nucleotide polymorphisms, a specialized analysis software (Affimetrix (GTYPE(registered trademark))) was used.

The total DNA extracted in Example 1 was treated in accordance with the instruction manuals of the kit and apparatus, and applied to a microarray, and a single nucleotide polymorphism existing on the DNA extracted from the specimen was analyzed. Briefly explaining, a sample obtained by treating 250 ng of a total DNA with a restriction enzyme NspI and a sample obtained by treating 250 ng of a total DNA with a restriction enzyme StyI were prepared, and amplified by a PCR method with adaptors bound to the protruding ends of each of the samples. A PCR product was collected, and fragmented with DNaseI, and the ends of the fragmented PCR products were biotin-labeled using the labeling reagent contained in the kit. A buffer for hybridization was added to the PCR products that were already fragmented at both ends and labeled, the mixture was heat-treated at 99° C. for 10 minutes, and incubated at 49° C. for 1 minute, and the resulting mixture was injected to a microarray for NspI-treated sample or a microarray for StyI-treated sample depending on a firstly treated restriction enzyme, and hybridized at 49° C. for 16 to 18 hours. After the termination of hybridization, the microarray was stained with streptavidin-phycoerythrin. A fluorescence from phycoerythrin bound via biotin and streptavidin to DNA ends of samples hybridized with an immobilized allele-specific probe was read using the scanner mentioned above, and analyzed with the software mentioned above. Probes corresponding to about 250,000 single nucleotide polymorphisms each are previously immobilized to the microarray for NspI-treated sample and the microarray for StyI-treated sample, respectively, and analytical results for about 500,000 single nucleotide polymorphisms per one sample were obtained by combination of both the results. According to the present method, opposite alleles of each of the single nucleotide polymorphisms were read with a single operation, and consequently, a genotype was determined. In this case, it was determined that the genotype was a heterozygote in a case where both signals from each of the alleles constituting a single nucleotide polymorphism were detected, and that the genotype was a homozygote of the detected allele in a case where only either one of the signals was detected.

Here, in accordance with the instruction manual of the kit, as the probe immobilized to the kit, a probe for a sense strand or a probe for an antisense strand of the genome is used. In addition, according to the datasheet of the kit, the determination results for the present kit using 270 samples and those in HapMap are compared for single nucleotide polymorphisms overlapping between single nucleotide polymorphisms reported in the HapMap project and single nucleotide polymorphisms in the kit. As a result, a concordance rate of the single nucleotide polymorphisms shows 99% or more.

Example 3 Comparison of Single Nucleotide Polymorphisms Between Glaucoma Patients and Non-Patients

The comparison on single nucleotide polymorphisms associated with a disease was made in accordance with the method used in the studies on genes responsible for age-related macular degeneration by Klein et al (Science, 308, 385, 2005).

Primary open-angle glaucoma patients and normal tension glaucoma patients that were diagnosed on the basis of Guidelines offered by Japan Glaucoma Society were assigned to a glaucoma patient group, and healthy individuals that were confirmed to have no family history of glaucoma according to a medical interview were assigned to a non-patient group. Blood donated under the consent on free will of the participants after having sufficiently explained the contents of studies from 418 cases of the glaucoma patient group and 300 controls of the non-patient group was used as specimens, a total DNA was extracted from the specimens according to the method described in Example 1, and the analysis of single nucleotide polymorphisms was performed according to the method described in Example 2. The analytical results of a single nucleotide polymorphism obtained in each of the patients were stored in the Laboratory Information Management System (World Fusion, LaboServer) adopting a relational database. A specialized analysis program for a single nucleotide polymorphism was created and loaded within the system, and the analysis was performed as follows: A single nucleotide polymorphism considered to have a high experimental reliability was extracted by rejecting a single nucleotide polymorphism having a call rate of less than 90% in both the glaucoma patient group and the non-patient group, a single nucleotide polymorphism having a difference in call rates between the glaucoma patient group and the non-patient group by 5% or more, a single nucleotide polymorphism having a minor allele frequency of less than 5%, and a single nucleotide polymorphism that is determined to deviate from the Hardy-Weinberg's equilibrium under conditions of a p-value of 1×10⁻⁴ or less according to a chi-square test, and allele frequencies and genotype frequencies of the single nucleotide polymorphisms were compared between the groups. The allele frequencies and the genotype frequencies were statistically compared according to the chi-square test. As to single nucleotide polymorphisms showing a p-value of 1×10⁻³ or less, cluster images serving as a basis for the determination of a genotype were confirmed. In a case where the determination of a genotype was made regardless of unclearness of the separation among clusters, the single nucleotide polymorphism was considered to be a non-subject of the analysis. In other words, the errors in the determination of a genotype were excluded by this step. The evaluation of the cluster was performed without informing the names of single nucleotide polymorphisms and the critical rates. Single nucleotide polymorphisms of which allele or genotype shows association with glaucoma at a p-value of 1×10⁻⁴ or less, i.e. −log P of 4 or more are listed in Tables 1 to 2. Here, the odds ratio for association of an allele with a disease, and the odds ratio for association of a genotype with a disease in each of the tables, respectively, were calculated on the basis of the following formulas (1) to (5).

Allele Frequency=Number of Detection of an Allele in Group/Total Number of Detection of Alleles in Group  formula (1)

Genotype Frequency=Number of Detection of a Genotype in Group/Total Number of Detection of Genotypes in Group  formula (2)

Odds Ratio for Allele=[(Number of Detection of an Allele Identified in High Frequency in Glaucoma Patient Group, in Glaucoma Patient Group)/(Number of Detection of an Allele Opposite to the Allele Identified in High Frequency in Glaucoma Patient Group, in Glaucoma Patient Group)]/[(Number of Detection of the Allele Identified in High Frequency in Glaucoma Patient Group, in Non-Patient Group)/(Number of Detection of the Allele Opposite to the Allele Identified in High Frequency in Glaucoma Patient Group, in Non-Patient Group)]  formula (3)

Odds Ratio for Genotype of Homozygote=[(Number of Detection of a Genotype Having Homozygote of an Allele Identified in High Frequency in Glaucoma Patient Group, in Glaucoma Patient Group)/(Number of Detection of a Genotype Having Homozygote of an Allele Identified in High Frequency in Non-Patient Group, in Glaucoma Patient Group)]/[(Number of Detection of the Genotype Having Homozygote of the Allele Identified in High Frequency in Glaucoma Patient Group, in Non-Patient Group)/(Number of Detection of the Genotype Having Homozygote of the Allele Identified in High Frequency in Non-Patient Group, in Non-Patient Group)]  formula (4)

Odds Ratio for Genotype of Heterozygote=[(Number of Detection of a Genotype of Heterozygote in Glaucoma Patient Group)/(Number of Detection of a Genotype Having Homozygote of an Allele Identified in High Frequency in Non-Patient Group, in Glaucoma Patient Group)]/[(Number of Detection of the Genotype Having Homozygote in Non-Patient Group)/(Number of Detection of the Genotype Having Homozygote of the Allele Identified in High Frequency in Non-Patient Group, in Non-Patient Group)]  formula (5)

TABLE 1 High-Risk Allele High-Risk Frequency Allele Critical in Frequency rate Glaucoma in Non- Allele 1/ Chromo- Physical Allele Patient Patient dbSNP ID Allele 2 Exon, Intron some Location (−logP) Group Group rs12632110 A/G SEMA3F Intron18 (NM_004186.2) 3 50199229 4.27 0.54 0.44 rs2233476 A/C CYB561D2 Exon1 (NM_007022.3) 3 50363387 5.57 0.55 0.42 rs9852677 C/T GNA12 Intron4 (NM_002070.1) 3 50266621 5.27 0.56 0.44 rs2236944 G/T GNA12 Intron4 (NM_002070.1) 3 50267197 5.00 0.55 0.43 rs6786523 A/G CACNA2D2 Intron2 (NM_006030.1) 3 50499225 4.05 0.60 0.49 rs1467913 G/T CACNA2D2 Intron2 (NM_006030.1) 3 50500021 4.22 0.60 0.50 rs2004243 A/G LOC51337 + 641 bp (NM_016647.1) 8 143815988 4.46 0.45 0.34 rs3761980 C/T SLC26A8 − 1529 bp (NM_052961.2), 6 36101884 4.12 0.93 0.87 SLC26A8 − 1636 bp (NM_138718.1) rs16884919 A/G MAPK14 Intron10 (NM_001315.1), 6 36179495 4.12 0.93 0.87 MAPK14 Intron10 (NM_139012.1), MAPK14 Intron9 (NM_139014.1), MAPK14 + 982 bp (NM_139013.1) rs16883860 C/T MAPK Intron1 (NM_139013.1), 6 36110440 4.42 0.94 0.87 MAPK Intron1 (NM_001315.1), MAPK Intron1 (NM_139012.1), MAPK Intron1 (NM 139014.1) rs10513095 G/T CLSTN2 Intron1 (NM_022131.1) 3 141219021 4.52 0.84 0.75 rs7081455 A/C PLXDC2 + 69770 bp (NM_032812.7) 10 20678891 4.33 0.83 0.74 rs7850541 C/T GBGT1 − 11253 bp (NM_021996.3) 9 133080108 4.15 0.76 0.66 rs10116267 C/T PSAT1 Intron5 (NM_021154.3), 9 78151286 4.24 0.78 0.69 PSAT1 Intron5 (NM_058179.2) rs10116231 A/G PSAT1 Intron5 (NM_021154.3), 9 78151153 4.11 0.78 0.69 PSAT1 Intron5 (NM_058179.2) rs6813301 G/T MGC45800 + 203455 bp (NM_178838.2) 4 183234501 4.16 0.12 0.06 rs11945595 C/T MGC45800 + 201900 bp (NM_178838.2) 4 183236056 4.07 0.12 0.06 rs2049723 A/G SPON1 − 17894 bp (NM_006108.1) 11 13922920 4.78 0.76 0.65 rs1159623 C/G CNTN5 Intron2 (NM_014361.2), 11 9877941 4.18 0.45 0.34 CNTN5 Intron2 (NM_175566.1) rs7109406 A/C CNTN5 Intron2 (NM_014361.2), 11 98867701 4.17 0.45 0.35 CNTN5 Intron2 (NM_175566.1) Critical rate, Odds Ratio Odds Ratio Sequence Sequence High-Risk Odds Ratio Genotype (Heterozygote1) (Heterozygote) Containing Containing dbSNP ID Allele (Formula 3) (-logP) (Formula 4) (Formula 5) Allele 1 Allele 2 rs12632110 Allele 1 1.54 3.60 2.34 1.71 SEQ ID NO: 1  SEQ ID NO: 2  rs2233476 Allele 1 1.66 4.91 2.74 1.84 SEQ ID NO: 3  SEQ ID NO: 4  rs9852677 Allele 2 1.63 4.62 2.70 1.80 SEQ ID NO: 5  SEQ ID NO: 6  rs2236944 Allele 2 1.61 4.41 2.60 1.84 SEQ ID NO: 7  SEQ ID NO: 8  rs6786523 Allele 1 1.53 3.60 2.46 1.80 SEQ ID NO: 9  SEQ ID NO: 10 rs1467913 Allele 2 1.54 3.73 2.49 1.79 SEQ ID NO: 11 SEQ ID NO: 12 rs2004243 Allele 1 1.58 3.85 2.25 1.78 SEQ ID NO: 13 SEQ ID NO: 14 rs3761980 Allele 2 2.05 3.48 6.40 3.13 SEQ ID NO: 15 SEQ ID NO: 16 rs16884919 Allele 2 2.05 3.48 6.40 3.13 SEQ ID NO: 17 SEQ ID NO: 18 rs16883860 Allele 2 2.14 3.74 6.41 3.00 SEQ ID NO: 19 SEQ ID NO: 20 rs10513095 Allele 2 1.73 3.73 3.02 1.74 SEQ ID NO: 21 SEQ ID NO: 22 rs7081455 Allele 1 1.70 3.91 1.91 0.98 SEQ ID NO: 23 SEQ ID NO: 24 rs7850541 Allele 1 1.60 3.89 3.35 2.33 SEQ ID NO: 25 SEQ ID NO: 26 rs10116267 Allele 1 1.63 3.50 2.18 1.24 SEQ ID NO: 27 SEQ ID NO: 28 rs10116231 Allele 2 1.61 3.37 2.18 1.26 SEQ ID NO: 29 SEQ ID NO: 30 rs6813301 Allele 2 2.24 3.67 2.07 2.45 SEQ ID NO: 31 SEQ ID NO: 32 rs11945595 Allele 2 2.24 3.57 2.04 2.45 SEQ ID NO: 33 SEQ ID NO: 34 rs2049723 Allele 1 1.66 3.96 2.87 1.83 SEQ ID NO: 35 SEQ ID NO: 36 rs1159623 Allele 2 1.55 3.88 2.21 1.84 SEQ ID NO: 37 SEQ ID NO: 38 rs7109406 Allele 2 1.55 4.01 2.17 1.89 SEQ ID NO: 39 SEQ ID NO: 40

TABLE 2 High-Risk High-Risk Allele Allele Critical Frequency Frequency Rate in Glaucoma in Non- Allele 1/ Chromo- Physical Allele Patient Patient dbSNP ID Allele 2 Exon, Intron some Location (−logP) Group Group rs4763559 C/G KLRA1 + 10130 bp (NM_006611.1) 12 10622909 4.48 0.75 0.65 rs4763531 A/G KLRA1 + 374 bp (NM_006611.1) 12 10629565 4.11 0.74 0.65 (rs9739469) rs2125094 C/T KLRA1 + 11027 bp (NM_006611.1) 12 10622012 4.38 0.74 0.64 rs2233476 A/C CYB561D2 Exon1 (NM_007022.3) 3 50363387 5.57 0.55 0.42 rs9852677 C/T GNA12 Intron4 (NM_002070.1) 3 50266621 5.27 0.56 0.44 rs2236944 G/T GNA12 Intron4 (NM_002070.1) 3 50267197 5.00 0.55 0.43 rs4430902 A/G GULP1 Intron1 (NM_016315.1) 2 189010443 3.57 0.85 0.77 rs10804020 C/T GULP1 Intron1 (NM_016315.1) 2 189028382 2.93 0.84 0.77 rs13137759 C/T DKFZp686L1814 Intron2 (NM_194282.1) 4 84262335 3.39 0.82 0.74 rs11737784 A/C DKFZp686L1814 − 11708bp (NM_194282.1) 4 84300869 3.15 0.81 0.74 rs9498701 C/T GRIK2 Intron6 (NM_021956.2), 6 102336911 0.93 0.59 0.55 GRIK2 Intron6 (NM_175768.1) rs9322609 A/G GRIK2 Intron8 (NM_021956.2), 6 102357540 0.67 0.58 0.55 GRIK2 Intron8 (NM_175768.1) rs10130333 A/C CHES1 Intron2 (NM_005197.1) 14 88929499 3.97 0.69 0.59 rs11133030 C/T FBXO8 + 139977 bp (NM_012180.1) 4 175392565 2.16 0.70 0.63 rs2220757 A/C BARX2 + 108243 bp (NM_003658.3) 11 128935268 1.34 0.71 0.66 rs7109406 A/C CNTN5 Intron2 (NM_014361.2), 11 98867701 4.17 0.45 0.35 CNTN5 Intron2 (NM_175566.1) rs2347897 C/T LOC402300 Intron2 (XM_377974), 7 133937842 2.98 0.39 0.31 CALD1 Intron1 (NM_004342.5), CALD1 Intron1 (NM_033138.2), CALD1 Intron1 (NM_033157.2), CALD1 − 95572 bp (NM_033139.2), CALD1 − 95572 bp (NM_033140.2), rs7794696 A/G LOC402300 Intron1 (XM_377974), 7 133961274 3.29 0.39 0.30 CALD1 Intron1 (NM_004342.5), CALD1 Intron1 (NM_033138.2) CALD1 Intron1 (NM_033157.2) CALD1 − 72140 bp (NM_033139.2), CALD1 − 72140 bp (NM_033140.2) rs803594 C/G VGLL2 − 7136 bp (NM_153453.1), 6 117686278 0.94 0.21 0.18 VGLL2 − 7152 bp (NM_182645.2) rs762164 A/C RUNX1 Intron5 (NM_001754.2) 21 35140644 0.52 0.44 0.42 Odds Odds Critical Ratio Ratio High- Odds Rate Homo- (Hetero- Sequence Sequence Risk Ratio Genotype zygote1 zygote) Containing Containing dbSNP ID Allele (Formula 3) (−1ogP) (Formula 4) (Formula 5) Allele 1 Allele 2 rs4763559 Allele 2 1.62 3.70 2.32 1.34 SEQ ID NO: 41 SEQ ID NO: 42 rs4763531 Allele 1 1.58 3.31 2.29 1.39 SEQ ID NO: 43 SEQ ID NO: 44 (rs9739469) rs2125094 Allele 1 1.61 3.59 2.34 1.37 SEQ ID NO: 45 SEQ ID NO: 46 rs2233476 Allele 1 1.66 4.91 2.75 1.84 SEQ ID NO: 47 SEQ ID NO: 48 rs9852677 Allele 2 1.63 4.62 2.70 1.80 SEQ ID NO: 49 SEQ ID NO: 50 rs2236944 Allele 2 1.61 4.41 2.60 1.84 SEQ ID NO: 51 SEQ ID NO: 52 rs4430902 Allele 1 1.64 4.48 1.14 0.54 SEQ ID NO: 53 SEQ ID NO: 54 rs10804020 Allele 1 1.54 4.10 1.02 0.50 SEQ ID NO: 55 SEQ ID NO: 56 rs13137759 Allele 2 1.58 4.23 1.32 0.64 SEQ ID NO: 57 SEQ ID NO: 58 rs11737784 Allele 2 1.54 4.14 1.25 0.61 SEQ ID NO: 59 SEQ ID NO: 60 rs9498701 Allele 2 1.19 4.10 1.17 0.57 SEQ ID NO: 61 SEQ ID NO: 62 rs9322609 Allele 2 1.14 4.04 1.11 0.55 SEQ ID NO: 63 SEQ ID NO: 64 rs10130333 Allele 1 1.54 4.36 2.73 2.46 SEQ ID NO: 65 SEQ ID NO: 66 rs11133030 Allele 1 1.36 4.01 2.46 2.79 SEQ ID NO: 67 SEQ ID NO: 68 rs2220757 Allele 2 1.26 4.03 0.95 0.50 SEQ ID NO: 69 SEQ ID NO: 70 rs7109406 Allele 2 1.55 4.01 2.17 1.89 SEQ ID NO: 71 SEQ ID NO: 72 rs2347897 Allele 1 1.45 4.05 1.58 2.02 SEQ ID NO: 73 SEQ ID NO: 74 rs7794696 Allele 2 1.49 4.01 1.67 1.99 SEQ ID NO: 75 SEQ ID NO: 76 rs803594 Allele 2 1.24 4.31 0.49 1.90 SEQ ID NO: 77 SEQ ID NO: 78 rs762164 Allele 2 1.12 4.02 1.05 1.98 SEQ ID NO: 79 SEQ ID NO: 80

Tables 1 and 2 list dbSNP ID number or Affimetrix Array ID number specifying known single nucleotide polymorphisms obtained, each of bases constituting Allele 1 and Allele 2, the exon, intron information (in a case where a single nucleotide polymorphism exists on a gene, the gene name and the exon or intron in which SNP exists are shown, and in a case where a single nucleotide polymorphism does not exist on a gene, neighboring genes and a distance between the gene and the single nucleotide polymorphism are shown), the chromosome number at which a single nucleotide polymorphism exists, the physical location of a single nucleotide polymorphism, the p-value for an allele according to a chi-square test (−log P), the high-risk allele frequencies in the glaucoma patient group and the non-patient group, the type of the high-risk allele (indicating whether the high-risk allele is Allele 1 or Allele 2), the odds ratio for an allele, the p-value for a genotype according to a chi-square test (−log P), the odds ratio for a genotype of a homozygote and the odds ratio for a genotype of a heterozygote, and SEQ ID NO of the sequence containing Allele 1 and Allele 2 in each of the polymorphic sites. Here, one of ordinary skill in the art can obtain the information for sequences or alleles of the single nucleotide polymorphisms from dbSNP ID number or Affimetrix array ID number mentioned above.

When the allele or genotype frequencies listed in Tables 1 to 2 were compared between the non-patients without family history and the glaucoma patients, a statistical difference was found. By determining an allele of any one of these single nucleotide polymorphisms, whether or not an allele that is identified in a higher frequency in the glaucoma patient group than that of the non-patient group exists in the sample can be determined.

Specifically, when a first single nucleotide polymorphism listed in Tables 1 and 2 is explained as an example, one polymorphic site exists in a nucleic acid molecule shown in SEQ ID NO: 1 or 2 occupying a gene locus homologous to each other. In detail, a single nucleotide polymorphism is associated with the onset of glaucoma, of which 31st base is either A (Allele 1) or G (Allele 2), wherein Allele 1 indicated as a high-risk allele, that is, an allele of being A in the single nucleotide polymorphism is identified in a high frequency in the glaucoma patient group. Further, using the odds ratio for an allele, or the odds ratio for a genotype of a homozygote and the odds ratio for a genotype of a heterozygote, the degree of which the risk of a disease increases can be predicted in a case of having the allele or genotype. Similarly, all the sequences disclosed in Tables 1 and 2 have a polymorphic site associated with glaucoma in the sequence, and one allele or at least one genotype in the polymorphic site is identified in a high frequency in the glaucoma patient group.

According to the above studies, 40 single nucleotide polymorphisms of which alleles or genotypes were associated with glaucoma at a p-value of 1×10⁻⁴ or less existing in clusters in relatively adjacent regions on the genome were found in 21 regions.

The allele or genotype identified in a high frequency in the glaucoma patient group of a single nucleotide polymorphism listed in Tables 1 and 2 can be used as a marker showing that an onset risk of glaucoma is high. On the other hand, an allele that is opposite to the allele or a genotype other than the genotype can be used as a marker showing that an onset risk of glaucoma is low.

Next, the surrounding regions and/or genes of the single nucleotide polymorphisms listed in Tables 1 and 2 were determined on the basis of the database provided by the HapMap project. In detail, regions in which single nucleotide polymorphisms that were considered to be in a linkage disequilibrium with the single nucleotide polymorphisms listed in Tables 1 and 2 exist were determined, on the basis of the linkage disequilibrium data in combination of the Japanese and the Chinese in the HapMap project.

Also, in a case where the single nucleotide polymorphism listed in Tables 1 and 2 exists in the linkage disequilibrium region containing the gene, the physical location and the gene name of the region were determined. On the other hand, in a case where the single nucleotide polymorphism listed in Tables 1 and 2 exists in the linkage disequilibrium region without containing the gene, only the physical location of the region was determined.

In addition, in a case where the single nucleotide polymorphism listed in Tables 1 and 2 exists on one gene beyond the linkage disequilibrium region, only the gene name was determined.

A single nucleotide polymorphism of which p-value is lowest in each region is considered to be a single nucleotide polymorphism representing the region. Tables 3 and 4 list a single nucleotide polymorphism representing the region, the chromosome number at which the region exists, the physical location of the region (start point and end point) and the gene name contained in the region.

TABLE 3 Representative SNP (SNP with Lowest Start Point of End Point of Genes p-value of Physical Physical Contained in the Region) Chromosome Location Location the Region rs16883860 6 36,014,367 36,248,614 SLC26A8 DPRXP2 MAPK14 MAPK13 rs2233476 3 49,952,596 50,516,561 RBM6 RBM5 SEMA3F GNAT1 SLC38A3 GNAI2 SEMA3B FLJ38608 C3orf45 IFRD2 HYAL3 NAT6 HYAL1 HYAL2 TUSC2 RASSF1 ZMYND10 TUSC4 CYB561D2 TMEM115 CACNA2D2 rs2004243 8 143,691,186 143,902,698 ARC AK092432 JRK PSCA LY6K LOC51337 C8orf55 SLURP1 LYPDC2 LYNX1 AK126845 LY6D LYPD2 rs10513095 3 — — CLSTN2 rs7081455 10 20,663,479 20,716,201 no gene rs7850541 9 134,756,557 135,192,865 TSC1 GFI1B LOC158078 GTF3C5 CEL CELP RALGDS GBGT1 OBP2B LOC286310 ABO LOC653163 SURF6

TABLE 4 Representative SNP (SNP with Chro- Start Point of End Point of Lowest p-value of mo- Physical Physical Genes Contained the Region) some Location Location in the Region rs7109406 11 — — CNTN5 rs4763559 12 10,535,930 10,724,935 LOC255308 KLRA1 FLJ10292 STYK1 rs10116267 9 — — PSAT1 rs6813301 4 183,058,962 183,243,277 LOC643296 rs2049723 11 13,851,048 14,245,926 SPON1 rs9498701 6 — — GRIK2 rs2233476 3 49,952,596 50,516,561 RBM6 RBM5 SEMA3F GNAT1 SLC38A3 GNAI2 SEMA3B FLJ38608 C3orf45 IFRD2 HYAL3 NAT6 HYAL1 HYAL2 TUSC2 RASSF1 ZMYND10 TUSC4 CYB561D2 TMEM115 CACNA2D2 rs10130333 14 88,697,458 89,155,209 CHES1 LOC646224 CAP2P1 LOC400236 rs4430902 2 188,904,662 189,286,159 GULP1 rs13137759 4 83,800,064 84,215,995 SCD4 SEC31L1 THAP9 DKFZp686L1814 COPS4 rs11133030 4 175,234,727 175,450,910 FBXO8 KIAA1712 rs762164 21 35,049,200 35,343,511 RUNX1 rs7109406 11 — — CNTN5 rs2220757 11 128,920,427 128,953,084 no gene rs803594 6 117,682,814 117,853,711 VGLL2 ROS1 rs2347897 7 — — CALD1

The region listed in Tables 3 and 4 is a region or gene considered to be linked with a single nucleotide polymorphism listed in Tables 3 and 4 which is associated with glaucoma in the present invention, and a single nucleotide polymorphism which exists in these regions or genes is considered to be linked with a single nucleotide polymorphism in the present invention. In other words, any single nucleotide polymorphisms which exist in these regions are linked with the single nucleotide polymorphism which exists in the region as listed in Tables 3 and 4, and any of these single nucleotide polymorphisms can be used in the prediction of a risk of glaucoma in the same manner.

Also, a single nucleotide polymorphism of which allele or genotype shows association with glaucoma at a p-value of 1×10⁻³ or less, i.e. −log P of 3 or more, is also listed in Tables 5 to 25.

TABLE 5 High- High- Risk Risk Allele Allele Odds Odds Fre- Fre- Critical Ratio Ratio Critical quency in quency Odds rate, (Homo- (Heter- Chro- rate, Glaucoma in Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs2139539 COL16A1 + 69 bp 1 31,786,872 3.99 0.87 0.80 1.75 3.81 7.12 4.52 (NM_001856.2) rs693421 ZP4 − 45155 bp 1 234,425,131 3.53 0.55 0.45 1.48 3.77 2.14 2.02 (NM_021186.2) rs2038845 CACNAIS Intron2 1 197,799,070 0.57 0.41 0.39 1.13 3.76 1.00 1.89 (NM_000069.1) rs4040617 LOC284591 Intron2 1 819,185 0.24 0.17 0.15 1.09 3.68 ND 0.75 (XM_211529) rs540782 ZP4 − 43104 bp 1 234,423,080 3.43 0.56 0.46 1.47 3.52 2.09 1.96 (NM_021186.2) rs2040073 LOC339442 − 148785 bp 1 38,498,317 3.58 0.38 0.29 1.52 3.38 1.93 1.80 (XM_378855) rs547984 ZP4 − 42951 bp 1 234,422,927 3.48 0.55 0.46 1.47 3.35 2.10 1.88 (NM_021186.2) rs10798882 PEF Intron1 1 31,777,640 3.52 0.86 0.79 1.67 3.35 6.05 3.84 (NM_012392.1) rs2499601 ZP4 − 50960 bp 1 234,430,936 3.24 0.55 0.46 1.45 3.23 2.05 1.89 (NM_021186.2) rs909002 COLI6A1 Intron44 1 31,808,728 3.47 0.84 0.77 1.63 3.19 4.38 2.94 (NM_001856.2) rs2147798 CACNA1S Intron3 1 197,793,475 1.22 0.56 0.51 1.22 3.14 1.58 2.09 (NM_000069.1) rs10752589 CSF3R − 53414 bp (NM_000760.2), CSF3R − 53414 bp (NM_156038.2), CSF3R − 53414 bp (NM_156039.2), CSF3R − 53414 bp (NM_172313.1) rs2236913 PSEN2 Intron5 1 223,380,860 0.61 0.35 0.33 1.14 3.13 0.88 1.74 (NM_000447.1), PSEN2 Intron5 (NM_012486.1) rs10518601 ELTD1 − 94220 bp 1 79,312,758 0.27 0.79 0.78 1.08 3.08 3.51 4.57 (XM_371262) rs17102821 ELTD1 − 89304 bp 1 79,307,842 0.28 0.80 0.78 1.09 3.08 3.52 4.57 (XM_371262) rs7525498 ELTD1 − 102412 bp 1 79,320,950 0.30 0.80 0.78 1.09 3.04 3.53 4.54 (XM_371262) rs2359112 MGC15882 + 194951 bp 1 34,548,776 0.58 0.30 0.27 1.15 3.03 5.23 0.86 (NM_032884.2) rs1892116 ELYS Intron2 1 243,406,363 3.15 0.75 0.67 1.49 2.91 2.89 2.07 (NM_175865.1), ELYS Intron2 (NM_015446.1) rs7524405 PEF Intron1 1 31,777,672 3.27 0.84 0.77 1.59 2.89 3.77 2.54 (NM_012392.1) rs704709 MGC39558 Intron8 1 231,947,005 3.45 0.61 0.52 1.48 2.83 2.20 1.39 (NM_152490.1) rs1951626 SERPINC1 − 5704 bp 1 170,623,758 3.34 0.38 0.30 1.49 2.66 2.33 1.43 (NM_000488.1) rs11163089 MGC34032 Intron4 1 75,490,567 3.31 0.85 0.77 1.61 2.55 2.70 1.75 (NM_152697.2) rs10430126 LOC388630 + 22072 bp 1 47,934,070 3.10 0.64 0.55 1.45 2.54 2.08 1.33 (XM_371250)

TABLE 6 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds Rate (Homo- (Hetero- Chro- Rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron somes Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs16865980 RNF144 + 120346 bp (NM_014746.2) 2 7,255,254 1.98 0.24 0.18 1.41 3.96 0.84 1.99 rs4953262 PRKCE Intron1 (NM_005400.2) 2 45,952,444 0.15 0.53 0.52 1.04 3.75 1.01 0.53 rs10170220 GULP1 Intron2 (NM_016315.1) 2 189,123,624 2.80 0.84 0.78 1.53 3.68 1.03 0.53 rs6717705 VIT Intron1 (NM_053276.2) 2 36,838,198 2.80 0.88 0.82 1.60 3.62 18.77 14.09 rs759428 VIT Intron1 (NM_053276.2) 2 36,844,694 2.76 0.88 0.82 1.59 3.58 18.68 14.12 rs4670589 VIT Intron1 (NM_053276.2) 2 36,840,872 2.72 0.88 0.82 1.59 3.57 18.77 14.29 rs10931358 GULP1 Intron2 (NM_016315.1) 2 189,096,087 2.69 0.84 0.77 1.52 3.55 1.02 0.53 rs11124532 VIT Intron1 (NM_053276.2) 2 36,840,580 2.65 0.88 0.82 1.58 3.50 18.48 14.14 rs828868 MGC22014 Intron8 (XM_371501) 2 74,236,159 3.37 0.66 0.57 1.47 3.48 2.06 1.10 rs11677028 LOC339789 Intron9 (NM_207358.1) 2 8,309,297 1.34 0.71 0.66 1.26 3.45 2.50 2.92 rs6431929 LOC339789 + 41877 bp (NM_207358.1) 2 8,255,994 1.22 0.69 0.65 1.24 3.43 2.32 2.78 rs2421844 SLC4A5 Intron5 (NM_033323.2), 2 74,451,749 3.42 0.48 0.38 1.48 3.43 2.39 1.13 SLC4A5 Intron5 (NM_133478.1), SLC4A5 Intron5 (NM_133479.1), SLC4A5 Intronl (NM_021196.2) rs7559118 FLJ34870 Intron4 (NM_207481.1) 2 133,706,762 2.37 0.64 0.56 1.37 3.34 2.15 2.25 rs17754672 PELI1 − 61125 bp (NM_020651.2) 2 64,312,259 2.49 0.24 0.17 1.49 3.27 6.36 1.11 rs7584987 QPCT + 129689 bp (NM_012413.2) 2 37,641,805 2.56 0.44 0.37 1.39 3.26 2.40 1.03 rs7571760 CDC42EP3 + 127985 bp (NM_006449.3) 2 37,654,409 3.06 0.40 0.31 1.46 3.13 2.69 1.17 rs6724538 QPCT + 127553 bp (NM_012413.2) 2 37,639,669 3.33 0.42 0.32 1.48 3.12 2.49 1.16 rs13387588 SLC4A5 Intron2 (NM_033323.2), 2 74,473,795 3.27 0.48 0.39 1.46 3.10 2.29 1.15 SLC4A5 Intron2 (NM_133478.1), SLC4A5 Intron2 (NM_133479.1), SLC4A5 − 19990 bp (NM_021196.2) rs7601299 SP110 Intron3 (NM_004509.2), 2 230,903,499 1.26 0.91 0.88 1.39 3.08 ND ND SP110 Intron3 (NM_080424.1), SP110 Intron3 (NM_004510.2)

TABLE 7 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quen-cy Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs1198825 RAMP1 − 3950 bp (NM_005855.1) 2 238,546,337 3.82 0.44 0.34 1.52 3.07 2.23 1.57 rs10930321 STK39 − 102538 bp (NM_013233.1) 2 169,032,150 3.70 0.44 0.34 1.51 3.04 2.42 1.40 SNP_A − 2170785 LTBP1 Intron2 (NM_206943.1), 2 33,090,031 1.24 0.78 0.73 1.27 3.01 3.21 3.52 LTBP1 − 181297 bp (NM_000627.2) 2 33,090,031 1.24 0.78 0.73 1.27 3.01 3.21 3.52 rs12611812 CNTNAP5 lntron3 (NM_130773.2), 2 124,776,344 1.80 0.59 0.52 1.30 3.00 1.52 0.79 CNTNAP5 Intron3 (NM_138996.1) rs11123034 CNTNAP5 Intron3 (NM_130773.2), 2 124,776,617 1.80 0.59 0.52 1.30 3.00 1.52 0.79 CNTNAP5 Intron3 (NM_138996.1) rs7581836 SLC4A5 − 7735 bp (NM_033323.2), 2 74,489,052 3.18 0.49 0.40 1.45 2.95 2.24 1.17 SLC4A5 − 7735 bp (NM_133478.1), SLC4A5 − 7735 bp (NM_133479.1), SLC4A5 − 35247 bp (NM_021196.2) rs4430896 KBTBD9 − 239670 bp (XM_496546) 2 23,246,431 3.58 0.75 0.66 1.54 2.94 1.91 1.12 rs7574012 QPCT + 126765 bp (NM_012413.2) 2 37,638,881 3.04 0.41 0.32 1.45 2.81 2.49 1.22 rs9309484 DCTN1 + 1471 bp (NM_023019.1), 2 74,498,466 3.06 0.49 0.40 1.44 2.77 2.16 1.16 DCTN1 + 1471 bp (NM_004082.2) rs4666488 ODD − 128777 bp (NM_145260.1) 2 19,608,777 3.13 0.36 0.28 1.48 2.67 1.90 1.65 rs3771738 SLC4A5 lntron5 (NM_033323.2), 2 74,452,572 3.04 0.48 0.40 1.43 2.65 2.14 1.19 SLC4A5 Intron5 (NM_133478.1), SLC4A5 Intron5 (NM_133479.1), SLC4A5 Intronl (NM_021196.2) rs4848607 FLJ14816 − 60027 bp (NM_032845.1) 2 120,999,954 3.28 0.75 0.66 1.50 2.58 2.33 1.61 rs4668312 LOC389059 − 20365 bp (XM_374017) 2 171,432,334 3.04 0.74 0.65 1.47 2.58 1.80 1.08 rs4411759 HTLF Intron2 (NM_002158.2) 2 48,468,133 3.16 0.55 0.46 1.44 2.57 2.07 1.57 rs2268794 SRD5A2 Intron1 (NM_000348.2) 2 31,691,055 3.01 0.20 0.13 1.63 2.55 5.02 1.46 rs11676168 HTLF Intron1 (NM_002158.2) 2 48,465,842 3.15 0.55 0.46 1.44 2.52 2.07 1.54

TABLE 8 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs4667649 SPS + 8390 bp 2 171,408,395 3.21 0.73 0.65 1.49 2.43 1.93 1.23 (XM_371581) rs6745010 LRP1B + 648365 bp 2 140,174,363 3.09 0.91 0.86 1.75 2.42 3.69 2.17 (NM_018557.1) rs2356232 SP5 + 2276 bp 2 171,412,281 3.19 0.73 0.65 1.49 2.41 1.92 1.23 (XM_371581) rs7608898 SP5 + 23719 bp 2 171,423,724 3.19 0.73 0.65 1.48 2.41 1.92 1.23 (XM_371581) rs10184230 LOC389059 − 25058 bp 2 171,427,641 3.19 0.73 0.65 1.48 2.41 1.92 1.23 (XM_374017) rs6433243 LOC389059 − 21697 bp 2 171,431,002 3.19 0.73 0.65 1.48 2.41 1.92 1.23 (XM_374017) rs10930437 SP5 + 6843 bp 2 171,406,848 3.15 0.73 0.64 1.48 2.40 1.92 1.22 (XM_371581) rs1566993 DPP10 + 503127 bp 2 116,821,290 3.13 0.96 0.91 2.10 2.40 4.55 2.22 (NM_020868.1) rs1990702 LRP2 + 8346 bp 2 169,802,022 3.04 0.71 0.63 1.46 2.36 2.00 1.32 (NM_004525.1) rs10183959 NEDL2 Intron1 2 197,139,030 3.15 0.93 0.88 1.89 2.35 3.17 1.72 (XM_038999) rs6746374 LOC389059 − 7686 bp 2 171,445,013 3.03 0.74 0.66 1.47 2.34 1.95 1.25 (XM_374017) rs6599252 SCN10A Intron12 3 38,764,695 0.14 0.48 0.47 1.04 3.94 1.17 0.56 (NM_006514.1) rs7612549 LOC285307 + 209732 bp 3 34,789,105 2.18 0.44 0.36 1.35 3.93 2.38 0.88 (XM_211837) rs1012728 FLJ22419 lntron4 3 21,519,300 2.60 0.49 0.41 1.39 3.84 1.76 2.08 (NM_024697.1) rs13097360 GBE1 − 805292 bp 3 82,698,727 1.55 0.82 0.77 1.34 3.22 0.56 0.32 (NM_000158.1) rs33954719 SGEF Intron6 3 155,359,077 1.70 0.65 0.58 1.30 3.07 2.09 2.33 (NM_015595.2) rs1462840 LOC285194 + 426618 bp 3 118,345,185 2.84 0.63 0.54 1.42 3.07 2.23 2.03 (XM_379207) rs17013665 LOC440947 − 8774 bp 3 23,718,507 3.79 0.71 0.62 1.53 3.05 2.42 1.69 (XM_496633) rs2044757 SGEF Intron5 3 155,352,950 1.58 0.65 0.59 1.28 3.05 2.03 2.32 (NM_015595.2) rs1503075 ALCAM − 79337 bp 3 106,289,543 3.46 0.13 0.07 1.93 3.01 ND 1.84 (NM_001627.1) rs6550308 L0C285307 + 332200 bp 3 34,911,573 3.08 0.48 0.39 1.44 2.98 1.90 1.78 (XM_211837) rs12494849 CACNA2D2 Intron2 3 50,499,562 3.61 0.59 0.49 1.48 2.89 2.20 1.52 (NM_006030.1) rs3755827 ZNF312 − 1350 bp 3 62,335,411 3.69 0.81 0.73 1.61 2.88 2.43 1.51 (NM_018008.2) rs9881866 ALCAM − 264171 bp 3 106,304,709 3.32 0.15 0.09 1.81 2.87 1.97 1.97 (NM_001627.1) rs34329202 LOC389099 − 54783 bp 3 22,240,837 3.37 0.92 0.86 1.83 2.82 1.99 1.01 (XM_371621) rs10935365 CLSTN2 Intron1 3 141,227,766 3.47 0.84 0.76 1.61 2.77 2.61 1.62 (NM_022131.1)

TABLE 8 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs2138789 GRK7 Intron2 3 142,991,449 3.33 0.14 0.08 1.86 2.67 3.28 1.88 (NM_139209.1) rs6550783 LOC440947 − 8191 bp 3 23,719,090 3.18 0.69 0.61 1.47 2.48 2.18 1.51 (XM_496633) rs779701 GRM7 Intron7 3 7,493,772 3.03 0.33 0.25 1.48 2.48 1.80 1.64 (NM_181875.1), GRM7 Intron7 (NM_000844.2), GRM7 lntron7 (NM_181874.1) rs2216524 ILIRAP Intron7 3 191,824,803 3.03 0.86 0.79 1.59 2.47 1.99 1.18 (NM_134470.2), IL1RAP lntron7 (NM_002182.2) rs3922704 FLJ31579 lntron3 3 112,983,875 3.06 0.88 0.82 1.66 2.44 2.09 1.20 (NM_153268.1) rs7641653 LOC389105 − 266407 bp 3 35,093,422 3.06 0.40 0.32 1.45 2.43 2.08 1.50 (XM_374037) rs2193877 IL1RAP Intron7 3 191,825,144 3.05 0.85 0.79 1.59 2.41 2.15 1.30 (NM_I34470.2), IL1RAP Intron7 (NM_002182.2) rs4624606 IL1RAP Intron9 3 191,836,948 3.07 0.84 0.78 1.58 2.40 2.50 1.59 (NM_002182.2), IL1RAP + 6172 bp (NM_134470.2) rs4858594 THRB Intron2 3 24,248,858 3.02 0.69 0.61 1.45 2.21 1.95 133 (NM_000461.2) rs10454254 LOC285441 Intron1 4 187,735,925 1.17 0.81 0.77 1.27 3.70 0.60 0.33 (XM_379295) rs13110551 CCRN4L − 116225 bp 4 140,178,323 2.59 0.58 0.50 1.38 3.56 2.22 2.18 (NM_012118.2) rs1503539 MAD2L1 + 168679 bp 4 121,169,516 3.91 0.38 0.28 1.56 3.53 3.05 1.40 (NM_002358.2) rs3804100 TLR2 Exon2 4 154,983,014 3.96 0.74 0.64 1.57 3.37 2.72 1.84 (NM_003264.2) rs4516662 CCRN4L − 116103 bp 4 140,178,445 2.22 0.57 0.50 1.34 3.27 2.08 2.12 (NM_012118.2) rs10009731 STX18 − 141961 bp 4 4,803,808 2.34 0.83 0.77 1.46 3.23 6.58 5.41 (NM_016930.2) rs7676755 CYP4V2 Intron2 4 187,490,196 0.68 0.80 0.78 1.18 3.22 3.26 4.09 (NM_207352.1) rs10517556 LOC391656 − 135832 bp 4 62,947,647 2.42 0.51 0.43 1.37 3.21 1.75 1.96 (XM_373027) rs16996478 UNC5C − 11150 bp 4 96,838,490 3.98 0.20 0.12 1.80 3.17 3.11 1.79 (NM_003728.2) rs10517578 LOC285533 Intron4 4 155,005,757 3.89 0.74 0.65 1.56 3.15 2.47 1.61 (NM_173662.1) rs34415360 L0C132391 − 118159 bp 4 117,081,308 3.45 0.29 0.21 1.57 3.01 3.26 1.28 (XM_497978) rs930438 CENPC1 + 97050 bp 4 68,069,912 3.27 0.82 0.75 1.57 2.84 3.33 2.31 (NM_001812.1)

TABLE 10 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs17279573 KIAA0922 + 22425 bp 4 154,937,893 3.34 0.68 0.60 1.48 2.74 2.31 1.66 (NM_015196.2) rs11727442 TLR2 − 23144 bp 4 154,943,527 3.42 0.69 0.60 1.49 2.73 2.22 1.49 (NM_003264.2) rs1027690 MAD2L1 + 191047 bp 4 121,147,148 3.22 0.43 0.34 1.46 2.63 2.24 1.45 (NM_002358.2) rs16891164 LOC441009 + 88767 bp 4 14,590,288 3.15 0.96 0.92 2.12   2.63 ND ND (XM_498965) rs13107767 LOC152519 + 6607 bp 4 47,886,619 3.44 0.60 0.50 1.47 2.62 2.07 1.39 (NM_207330.1) rs1980391 LOC389239 − 207565 bp 4 165,986,419 3.18 0.62 0.53 1.45 2.60 1.99 1.23 (XM_371714) rs7376639 LOC132391 − 82192 bp 4 117,117,275 3.04 0.29 0.21 1.52 2.56 2.90 1.27 (XM_497978) rs4256218 SCD4 Introm1 4 84,047,858 3.28 0.89 0.82 1.69 2.55 2.70 1.59 (NM_024906.1) rs972469 FSTL5 + 959616 bp 4 161,703,038 3.06 0.40 0.32 1.45 2.47 2.27 1.36 (NM_020116.2) rs6829490 TXK + 894 bp 4 47,908,795 3.23 0.57 0.48 1.45 2.46 2.04 1.46 (NM_003328.1) rs3804099 TLR2 Exon2 4 154,982,261 3.07 0.71 0.63 1.46 2.45 2.24 1.57 (NM_003264.2) rs4392496 KIAA0922 Intron3 4 154,800,110 3.10 0.46 0.37 1.44 2.41 2.04 1.47 (NM_015196.2) rs4568220 LOC344988 Intron2 4 121,413,055 3.23 0.11 0.06 2.04 2.40 3.19 2.00 (XM_293671) rs33964061 TXK + 1806 bp 4 47,907,883 3.11 0.57 0.48 1.43 2.34 2.00 1.46 (NM_003328.1) rs6447614 TXK + 804bp 4 47,908,885 3.11 0.57 0.48 1.43 2.34 2.00 1.46 (NM_003328.1) rs12655405 PDZK3 − 33552 bp 5 31,801,198 0.80 0.93 0.91 1.33 3.88 0.13 0.06 (NM_015022.2), PDZK3 − 33552 bp (NM_178140.1) rs4515309 NNT + 296580 bp 5 44,037,927 1.77 0.12 0.08 1.56 3.74 0.00 2.02 (NM_012343.2), NNT + 296836 bp (NM_182977.1) rs1377489 MTRR + 135148 bp 5 8,089,385 1.15 0.82 0.78 1.28 3.56 20.15 19.82 (NM_024010.1), MTRR + 135148 bp (NM_002454.1) rs309593 CSPG2 Intron10 5 82,884,337 3.95 0.43 0.33 1.54 3.45 2.43 1.64 (NM_004385.2) rs6579788 TCOF1 − 25018 bp 5 149,692,410 1.15 0.37 0.32 1.23 3.43 2.27 0.80 (NM_000356.1) rs6451268 FLJ25422 Intron11 5 36,291,121 1.39 0.61 0.56 1.25 3.38 1.85 2.30 (NM_145000.2) rs529279 C5orf13 − 5941 bp 5 111,126,776 3.20 0.30 0.22 1.53 2.90 3.30 1.31 (NM_004772.1) rs298091 PDE4D − 114328 bp 5 59,032,360 3.58 0.82 0.74 1.61 2.86 2.37 1.43 (NM_0062039) rs3097776 FAT2 lntron2 5 150,916,554 3.34 0.72 0.63 1.49 2.77 2.01 1.23 (NM_001447.1) rs11750584 FLJ40243 − 22454 bp 5 41,129,616 3.13 0.20 0.13 1.64 2.68 1.86 1.80 (NM_173489.2)

TABLE 11 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−1ogP) Group Group mula 3) (−1ogP) mula 4) mula 5) rs11748095 FBXL17 − 103066 bp (NM_022824.1) 5 107,848,076 3.18 0.50 0.41 1.45 2.66 1.95 1.66 rs1428470 LY64 − 8157 bp (NM_005582.1) 5 66,536,525 3.15 0.80 0.72 1.53 2.64 1.93 1.16 rs11167493 CSF1R + 19417 bp (NM_005211.2) 5 149,393,634 3.02 0.12 0.07 1.92   2.52 ND 1.77 rs6891720 LY64 − 7944 bp (NM_005582.1) 5 66,536,312 3.04 0.80 0.72 1.51 2.52 1.91 1.16 rs4246764 LY64 − 384319 bp (NM_005582.1) 5 66,912,687 3.00 0.29 0.21 1.51 2.46 2.43 1.54 rs429419 ADAMTS12 Intron17 (NM_030955.1) 5 33,624,092 3.12 0.91 0.85 1.76 2.44 3.75 2.20 rs298063 PDE4D − 88343 bp (NM_006203.3) 5 59,006,375 3.15 0.82 0.75 1.55 2.44 2.11 1.32 rs818725 ADAMTS12 Intron17 (NM_030955.1) 5 33,624,060 3.05 0.91 0.86 1.74 2.37 3.66 2.17 rs4285312 NEDD9 − 191677 bp (NM_006403.2) 6 11,532,564 3.28 0.16 0.10 1.76 3.87 1.07 2.27 NEDD9 − 191687 bp (NM_182966.1) rs4840196 GRIK2 Intron8 (NM_021956.2), 6 102,359,520 0.96 0.60 0.55 1.19 3.72 1.19 0.60 GRIK2 Intron8 (NM_175768.1) rs4075603 NEDD9 − 191609 bp (NM_006403.2), 6 11,532,496 3.09 0.16 0.10 1.73 3.67 1.04 2.22 NEDD9 − 191619 bp (NM_182966.1) rs2764236 GRIK2 Intron9 (NM_021956.2), 6 102,389,150 0.83 0.59 0.56 1.17 3.61 1.15 0.59 GRIK2 Intron9 (NM_175768.1) rs4840195 GRIK2 Intron8 (NM_021956.2), 6 102,359,490 0.84 0.59 0.55 1.17 3.55 1.18 0.60 GRIK2 Intron8 (NM_175768.1) rs372534 AOF1Intron8 (XM_173173) 6 18,295,895 3.02 0.68 0.59 1.45 3.50 2.40 2.31 rs6907963 LOC442154 Intron1 (XM_498036) 6 4,903,481 2.45 0.88 0.83 1.56 3.18 16.95 13.09 rs6916915 EGFL11 − 135926 bp (NM_198283.1) 6 66,398,533 3.44 0.54 0.45 1.47 3.08 2.18 1.20 rs3857597 LOC442216 − 86680 bp (XM_498099) 6 51,020,014 3.84 0.22 0.14 1.73 3.07 2.60 1.76 rs902287 EGFL11 − 127786 bp (NM_198283.1) 6 66,390,393 3.31 0.51 0.42 1.46 3.05 2.19 1.16 rs7761118 MAPK14 Intron9 (NM_139013.1), 6 66,390,393 3.31 0.51 0.42 1.46 3.05 2.19 1.16 MAPK14 Intron9 (NM_001315.1), MAPK14 Intron9 (NM_139012.1), 6 36,176,281 3.63 0.93 0.87 1.95 3.05 4.77 2.39 MAPK14 Intron9 (NM_139014.1)

TABLE 12 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−1ogP) Group Group mula 3) (−1ogP) mula 4) mula 5) rs9473926 LOC442216 − 10440 bp (XM_498099) 6 50,943,774 330 0.54 0.45 1.46 2.90 2.17 1.69 rs1206153 KIAA1900 Intron6 (NM_052904.1) 6 97,652,757 3.02 0.56 0.47 1.43 2.80 1.95 1.08 rs16871306 NEDD9 − 153598 bp (NM_006403.2), 6 11,494,485 3.04 0.09 0.04 2.17   2.52 ND 2.22 NEDD9 − 153608 bp (NM_182966.1) rs9398995 ENPP1 Intron1 (NM_006208.1) 6 132,181,896 3.12 0.58 0.48 1.44 2.51 2.06 1.59 rs9358578 LOC389370 Intron1 (XM_374162) 6 22,810,626 3.27 0.44 0.35 1.47 2.46 2.12 1.39 rs10488281 PRES Intron2 (NM_206883.1), 7 102,663,783 1.13 0.48 0.44 1.21 3.64 1.66 0.72 PRES Intron2 (NM_206884.1), PRES Intron2 (NM_206885.1), PRES Intron2 (NM_198999.1) rs2215164 COBL Intron1 (NM_015198.2) 7 51,093,537 1.75 0.88 0.83 1.44 3.60 0.32 0.17 rs2299257 PON1 Intron4 (NM_000446.3) 7 94,587,416 3.65 0.37 0.28 1.54 3.43 2.01 1.80 rs1075737 PRES Intron2 (NM_206883.1), 7 102,665,144 0.99 0.48 0.44 1.19 3.41 1.60 0.72 PRES Intron2 (NM_206884.1), PRES Intron2 (NM_206885.1), PRES Intron2 (NM_198999.1) rs10232532 CPA5 − 3205 bp (NM_080385.2) 7 129,575,431 0.30 0.52 0.50 1.07 3.24 1.18 1.94 rs3917538 PON1 Intron5 (NM_000446.3) 7 94,582,544 3.50 0.51 0.42 1.47 3.16 2.20 1.16 rs1222418 FLJ32786 Intron12 (NM_144648.1) 7 133,334,253 3.72 0.17 0.10 1.89 3.14 10.10 1.72 rs2966701 TAS2R41 + 27695 bp (NM_176883.1) 7 142,720,419 3.59 0.13 0.07 2.01 3.13 2.48 2.15 rs10271531 HGF + 217504 bp (NM _000601.3) 7 80,758,592 3.78 0.42 0.33 1.52 3.11 2.46 1.41 rs12700287 DNAH11 Intron8 (NM_003777.1) 7 21,385,860 3.76 0.96 0.92 2.39   3.10 ND ND rs10228385 LOC401324 + 47600 bp (XM_379484) 7 35,236,926 3.79 0.84 0.76 1.65 3.07 2.21 1.26 rs4726533 PRSS1 − 172004 bp (NM_002769.2) 7 141,771,615 0.57 0.39 0.36 1.13 3.07 1.71 0.72

TABLE 13 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−1ogP) Group Group mula 3) (−1ogP) mula 4) mula 5) rs2285652 OSBPL3 Intron22 (NM_015550.2), 7 24,617,110 3.56 0.84 0.77 1.64 3.02 3.55 2.33 OSBPL3 lntron2l (NM_145320.1), OSBPL3 Intron21 (NM_145321.1), OSBPL3 Intron20 (NM 145322.1), OSBPL3 Intron22 (NM_145323.1), OSBPL3 Intron21 (NM_145324.1) rs10250170 TPK1 Intron8 (NM_022445.2) 7 143,650,537 0.69 0.12 0.10 1.24 3.02 0.11 1.67 rs2966712 TAS2R41 − 7843 bp (NM_176883.1) 7 142,683,960 3.22 0.11 0.06 1.97 3.02 0.82 2.20 rs1001148 COBL Intron1 (NM_015198.2) 7 51,094,084 1.40 0.88 0.84 1.37 3.01 0.32 0.18 rs17167646 FLJ32786 Intron16 (NM_144648.1) 7 133,365,708 3.50 0.15 0.09 1.84 2.93 9.85 1.66 rs930688 FLJ32786 Intron16 (NM_144648.1) 7 133,366,047 3.50 0.15 0.09 1.84 2.93 9.85 1.66 rs991162 FLJ32110 − 9270 bp (NM_181646.2) 7 88,024,134 3.55 0.15 0.09 1.89 2.91 2.49 1.98 rs2592845 LOC401324 + 94391 bp (XM_379484) 7 35,283,717 3.07 0.77 0.69 1.51 2.90 3.17 2.30 rs10228514 LOC401324 + 47709 bp (XM_379484) 7 35,237,035 3.55 0.83 0.75 1.62 2.86 2.20 1.30 rs10488110 LOC340268 Intron1 (XM_294634) 7 9,827,710 3.41 0.11 0.06 2.07   2.81 ND 1.89 rs975910 HIC + 252683 bp (NM_199072.2) 7 114,505,890 3.53 0.94 0.88 1.98 2.72 5.49 3.05 rs2893506 LOC401324 +25585 bp (XM_379484) 7 35,214,911 3.52 0.83 0.75 1.60 2.69 2.47 1.58 rs10236415 LOC401324 + 28462 bp (XM_379484) 7 35,217,788 3.52 0.83 0.75 1.60 2.69 2.47 1.58 rs9640055 GLCCII Intron1 (XM_166519) 7 7,802,756 3.27 0.82 0.75 1.57 2.65 2.55 1.62 rs2592860 LOC401324 + 14726 bp (XM_379484) 7 35,204,052 3.25 0.71 0.63 1.48 2.52 2.15 1.45 rs16961391 NUP205 − 1742 bp (XM_371954) 7 134,698,206 3.12 0.73 0.65 1.47 2.52 2.11 1.36 rs115357 FLJ3842 + 130801 bp (NM_024645.1) 8 40,376,469 1.62 0.31 0.25 1.32 3.49 1.01 1.90 rs2977752 L0C441352 + 55834 bp (XM_499115) 8 72,715,809 1.84 0.58 0.52 1.30 3.39 1.87 2.19 rs10504440 LOC389667 + 50257 bp (XM_372046) 8 70,255,391 2.06 0.70 0.64 1.35 3.32 2.77 2.73 rs2470722 GEM − 2381bp (NM_005261.2), 8 95,346,114 1.12 0.77 0.73 1.25 3.28 0.79 0.45 GEM − 2381bp (NM_181702.1)

TABLE 14 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs12898 CTSB + 629 bp (NM_001908.2), 8 11,738,607 2.92 0.49 0.40 1.42 3.27 1.81 1.90 CTSB + 629 bp (NM_147780.1), CTSB + 629 bp (NM_147781.1), CTSB + 629 bp (NM_147782.1), CTSB + 629 bp (NM 147783.1) rs6991723 ZNF596 + 33933 bp (NM_173539.1) 8 221,272 2.75 0.58 0.49 1.40 3.25 2.08 2.04 rs16904092 MGC27434 Intron1 (NM_145050.2) 8 130,571,112 1.05 0.90 0.87 1.33 3.19 0.16 0.09 rs6468360 LOC286135 − 35034 bp (XM_379573) 8 29,863,536 2.01 0.55 0.48 1.32 3.16 1.78 0.86 rs4736872 FLJ3842 Intron5 (NM_024645.1) 8 40,570,858 0.36 0.63 0.61 1.09 3.12 1.54 2.26 rs10958627 FLJ13842 Intron5 (NM_024645.1) 8 40,594,675 0.03 0.47 0.47 1.01 3.08 0.96 1.75 rs16935718 LOC389667 + 60391 bp (XM_372046) 8 70,265,525 1.87 0.74 0.68 1.34 3.07 3.16 3.04 rs1605950 PXMP3 − 574113 bp (NM_000318.1) 8 78,649,107 0.82 0.28 0.25 1.19 3.07 0.78 1.73 rs2513858 STARS − 43515 bp (NM_139166.2) 8 107,895,164 0.07 0.65 0.65 1.02 3.05 1.49 2.29 rs16935744 LOC389667 + 75414 bp (XM_372046) 8 70,280,548 1.80 0.74 0.68 1.33 3.04 3.05 2.98 rs2272767 CTSB Intron1 (NM_001908.2), 8 11,748,468 2.69 0.48 0.40 1.40 3.01 1.75 1.85 CTSB Intron3 (NM_147780.1), CTSB Intron2 (NM_147781.1), CTSB Intron2 (NM_147782.1), CTSB Intron2 (NM 147783.1) rs705998 LOC389667 + 90010 bp (XM_372046) 8 70,295,144 1.55 0.71 0.65 1.29 3.01 2.51 2.69 rs12545915 SNTG1 Intron2 (NM_018967.1) 8 51,329,479 3.39 0.85 0.77 1.62 2.91 1.82 1.01 rs6999627 SNTG1 Intron2 (NM_018967.1) 8 51,340,728 3.27 0.85 0.78 1.61 2.77 1.81 1.02 rs3757916 RBPMS Intron9 (NM_0061167.1) 8 30,545,447 3.10 0.43 0.34 1.45 2.62 1.96 1.62 rs2729482 LOC169355 Intron9 (NM_194294.1) 8 39,975,804 3.50 0.11 0.06 2.07 2.61 3.62 2.00 rs7823902 LOC286129 Intron2 (XM_209910) 8 26,963,854 3.20 0.34 0.26 1.50 2.58 2.12 1.56 rs11783765 GTF2E2 Intron7 (NM_002095.3) 8 30,556,550 3.12 0.40 0.32 1.46 2.55 2.17 1.51

TABLE 15 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs17758599 SNTG1 Intron1 8 51,109,255 3.14 0.85 0.78 1.59 2.49 2.77 1.78 (NM_018967.1) rs2468705 KCNK9 + 75721 bp 8 140,618,265 3.08 0.28 0.20 1.53 2.45 2.48 1.52 (NM_016601.2) rs6474298 FLJ3842 − 168006 bp 8 41,042,506 3.23 0.81 0.73 1.55 2.45 2.27 1.48 (NM_024645.1) rs17473451 TUSC3 − 73601 bp 8 15,368,500 3.05 0.79 0.71 1.51 2.43 1.98 1.24 (NM_006765.2), TUSC3 − 73601 bp (NM_178234.1) rs6559770 SLC28A3 + 116711 bp 9 84,005,935 2.83 0.47 0.38 1.41 3.55 1.82 1.96 (NM_022127.1) rs10984339 LOC442434 + 182746 bp 9 118,798,668 1.63 0.42 0.36 1.28 3.18 1.34 1.89 (XM_498343) rs920753 LOC389771 − 178380 bp 9 89,862,442 0.11 0.27 0.26 1.04 3.13 0.55 1.55 (XM_374296) rs411102 LOC347265 + 48076 bp) 9 99,196,524 3.28 0.16 0.10 1.79 3.06 1.50 2.03 (XM_294590 rs1342022 ANXA1 − 61274 bp 9 72,935,061 1.37 0.60 0.54 1.24 3.05 1.34 0.71 (NM_000700.1) rs10972299 VCP + 4230 bp 9 35,042,331 3.54 0.95 0.89 2.09 3.01 2.57 15.88 (NM_007126.2) rs303612 LOC340511 − 47888 bp 9 103,142,991 0.20 0.61 0.59 1.05 3.01 1.39 2.12 (XM_295261) rs1316814 BARX1 − 25445 bp 9 93,822,273 3.20 0.57 0.48 1.45 2.80 2.27 1.60 (NM_021570.2) rs1538844 JMJD2C Intron8 9 6,953,799 3.07 0.41 0.33 1.46 2.78 1.91 1.70 (NM_015061.1) rs2148591 PCSK5 − 63459 bp 9 75,671,716 3.11 0.45 0.36 1.45 2.72 2.28 1.21 (NM_006200.2) rs932881 JMJD2C + 1849 bp 9 7,167,496 3.25 0.78 0.70 1.52 2.53 2.37 1.61 (NM_015061.1) rs10764881 MGMT − 70674 bp 10 131,153,821 0.91 0.72 0.68 1.20 3.94 5.56 6.03 (NM_002412.1) rs1649035 TFAM + 176804 bp 10 60,002,707 3.82 0.61 0.51 1.51 3.94 2.56 2.09 (NM_003201.1), TFAM + 187289 bp (NM_012251.1) rs782394 LOC387721 − 251645 bp 10 130,349,442 2.06 0.54 0.47 1.33 3.70 1.75 0.80 (XM_370585) rs1649048 TFAM + 168385 bp 10 59,994,288 3.54 0.60 0.51 1.48 3.54 2.36 1.99 (NM_003201.1), TFAM + 178870 bp (NM_012251.1) rs7477330 TFAM + 162217 bp 10 59,988,120 3.63 0.60 0.51 1.49 3.52 2.38 1.95 (NM_003201.1), TFAM + 172702 bp (NM_012251.1 rs17157033 LOC439960 − 30545 bp 10 44,613,470 2.88 0.96 0.92 2.14   3.45 ND ND (XM_498478) rs10458653 PCBD − 54076 bp 10 72,369,768 0.63 0.25 0.22 1.16 3.45 5.56 0.82 (NM_000281.1)

TABLE 16 High-Risk High-Risk Allele Allele Fre- Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−logP) Group Group mula 3) (−logP) mula 4) mula 5) rs3849969 SEC24C Intron12 (NM_004922.2), 10 75,196,005 3.36 0.27 0.19 1.57 3.44 1.58 1.92 SEC24C Intron11 (NM_198597.1) rs1658438 TFAM + 170686 bp (NM_003201.1), 10 59,996,589 3.56 0.60 0.51 1.48 3.43 2.35 1.92 TFAM + 181171 bp (NM_012251.1) rs1649039 TFAM + 174144 bp (NM_003201.1), 10 60,000,047 3.59 0.60 0.50 1.48 3.43 2.34 1.91 TFAM + 184629 bp (NM_012251.1) rs1658456 TFAM + 148429 bp (NM_003201.1), 10 59,974,332 3.54 0.60 0.51 1.48 3.40 2.33 1.91 TFAM + 158914 bp (NM_012251.1) rs1649060 TFAM + 154583 bp (NM_003201.1), 10 59,980,486 3.54 0.60 0.51 1.48 3.40 2.33 1.91 TFAM + 165068 bp (NM_012251.1) rs17130394 HABP2 − 103263 bp (NM_004132.2) 10 115,199,512 3.18 0.84 0.77 1.59 3.40 1.38 0.71 rs10763558 TFAM + 186037 bp (NM_003201.1), TFAM + 196522 bp (NM_012251.1) 10 60,011,940 3.62 0.60 0.50 1.49 3.36 2.33 1.87 rs10763556 TFAM + 185501 bp (NM_003201.1), 10 60,011,404 3.53 0.60 0.50 1.48 3.34 2.33 1.89 TFAM + 195986 bp (NM_012251.1) rs7902091 CTNNA3 Intron7 (NM_013266.1) 10 68,268,298 2.66 0.51 0.43 1.39 3.33 1.98 0.94 rs1210065 TMEM23 Intron5 (NM_147156.3) 10 51,882,795 2.61 0.41 0.34 1.40 3.31 1.59 1.89 rs10994838 ACF Intron1 (NM_014576.2), 10 52,312,506 1.16 0.36 0.32 1.23 3.31 2.21 0.80 ACF Intronl (NM_138932.1), ACF Intronl (NM_138933.1) rs11189912 SH2D4B + 793340 bp (NM_207372.1) 10 83,189,636 3.27 0.92 0.86 1.83 3.15 1.07 0.52 rs1028534 TMEM23 Intron3 (NM_147156.3) 10 51,898,627 2.47 0.66 0.59 1.38 3.10 2.22 2.21 rs1203392 TMEM23 Intron5 (NM_147156.3) 10 51,874,999 2.46 0.41 0.34 1.38 3.08 1.37 1.85 rs7910849 LOC220929 + 29028 bp (NM_182755.1) 10 31,144,546 3.06 0.74 0.66 1.48 3.08 1.69 0.93 rs7904101 TMEM23 − 7099 bp (NM_147156.3) 10 52,060,842 1.38 0.37 0.32 1.26 3.05 1.12 1.81 rs4474374 LOC439991 − 14752 bp (XM_495838) 10 85,647,711 0.14 0.33 0.32 1.04 3.05 1.98 0.69 rs11016249 MK167 − 323870 bp (NM_002417.2) 10 130,138,328 3.24 0.69 0.60 1.47 2.90 2.42 1.91

TABLE 17 High-Risk High-Risk Allele Allele Fre Fre- Odds Odds quency quency Critical Ratio Ratio Critical in in Odds rate, (Homo- (Heter- Chro- rate, Glaucoma Non- Ratio Geno- zygote) zygote) mo- Physical Allele Patient Patient (For- type (For- (For- dbSNP ID Exon, Intron some Location (−1ogP) Group Group mula 3) (−logP) mula 4) mula 5) rs2092832 SH2D4B + 843746 bp (NM_207372.1) 10 83,240,042 3.58 0.94 0.88 1.99 2.88 3.15 1.55 rs4934425 ANKRD22 Intron1 (NM_144590.1) 10 90,599,698 3.05 0.64 0.55 1.44 2.83 2.29 1.86 rs2688612 PLAU − 17730 bp (NM_052658.1) 10 75,323,211 3.57 0.42 0.33 1.50 2.81 2.28 1.45 rs10883820 CNNM2 Intron1 (NM_017649.3), 10 104,754,651 3.37 0.90 0.84 1.76 2.78 2.47 1.34 CNNM2 Intron1 (NM_199076.1), CNNM2 + 77286 bp (NM_199077.1) rs7074084 TFAM + 146618 bp (NM_003201.1), 10 59,972,521 3.20 0.59 0.49 1.44 2.77 2.16 1.69 TFAM + 157103 bp (NM_012251.1) rs1649023 TFAM + 129923 bp (NM_003201.1), 10 59,955,826 3.11 0.59 0.50 1.44 2.69 2.13 1.69 TFAM + 140408 bp (NM_012251.1) rs1649080 TFAM + 137397 bp (NM_003201.1), 10 59,963,300 3.11 0.59 0.50 1.44 2.69 2.13 1.69 TFAM + 147882 bp (NM_012251.1) rs1303970 TFAM + 142580 bp (NM_003201.1), 10 59,968,483 3.11 0.59 0.50 1.44 2.69 2.13 1.69 TFAM + 153065 bp (NM_012251.1) rs3829154 ECHDC3 − 1630 bp (NM_024693.2) 10 11,822,759 3.17 0.49 0.40 1.44 2.61 2.16 1.29 rs1926029 NT5C2 Intron11 (NM_012229.2) 10 104,845,660 3.20 0.91 0.85 1.75 2.57 3.18 1.80 rs2802493 LOC283034 + 233953 bp (XM_210860) 10 43,873,589 3.15 0.39 0.31 1.47 2.50 2.27 1.38 rs718641 ECHDC3 − 4475 bp (NM_024693.2) 10 11,819,914 3.08 0.49 0.40 1.44 2.49 2.12 1.30 rs7913781 ZWINT − 792415 bp (NM_007057.2), 10 58,583,444 3.22 0.18 0.11 1.72 2.46 4.17 1.49 ZWINT − 792415 bp (NM_032997.1) rs7894588 CNNM2 Intron1 (NM_017649.3), 10 104,746,020 3.08 0.91 0.85 1.72 2.46 2.41 1.35 CNNM2 Intron1 (NM_199076.1), CNNM2 + 68655 bp (NM_199077.1) rs1569868 SH2D4B + 852561 bp (NM_207372.1) 10 83,248,857 3.13 0.93 0.88 1.88 2.45 3.12 1.65 rs10883843 NT5C2 − 6408 bp (NM_012229.2) 10 104,937,483 3.03 0.91 0.85 1.71 2.41 2.39 1.35 rs7074395 NT5C2 +302984 bp (NM_012229.2) 10 104,834,918 3.00 0.91 0.85 1.71 2.39 2.39 1.35

High- Risk High- Allele Risk Fre- Allele Odds Odds Cri- quency Fre- Critical Ratio Ratio tical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs10829630 MGMT + 6919 bp (NM_002412.1) 10 131,462,275 3.02 0.58 0.49 1.43 2.21 1.96 1.40 rs923811 BARX2 + 93402 bp (NM_003658.3) 11 128,920,427 0.82 0.67 0.63 1.17 3.76 0.91 0.49 rs4937431 BARX2 + 124127 bp (NM_003658.3) 11 128,951,152 1.56 0.44 0.38 1.27 3.24 2.05 0.85 rs11021202 MGC33371 + 224211 bp (NM_144664.3) 11  94,917,555 3.28 0.14 0.08 1.85 3.18 1.33 2.17 rs497776 MAML2 Intron1 (NM_032427.1) 11  95,597,312 2.23 0.80 0.74 1.42 3.06 3.58 3.31 rs11602121 LOC399921 Intron4 (XM_374904) 11  70,237,526 1.45 0.29 0.24 1.30 3.00 5.91 1.01 rs 11220171 CNTN5 Intron2 (NM_014361.2), 11  98,866,995 3.46 0.36 0.28 1.51 2.95 2.04 1.67 CNTN5 Intron2 (NM_175566.1) rs4307718 LOC440033 + 175532 bp (XM_498512) 11  23,320,437 3.48 0.96 0.92 2.27 2.90 ND ND rs1384483 LOC440033 + 63001 bp (XM_498512) 11  23,207,906 3.23 0.13 0.07 1.90 2.78 ND 1.79 rs500629 ZBTB16 Intron3 (NM_006006.3) 11 113,550,770 3.13 0.29 0.22 1.52 2.72 1.88 1.69 rs1507527 LOC387754 − 33940 bp (XM_373490) 11  13,882,655 3.25 0.77 0.69 1.51 2.72 2.23 1.39 rs2007052 SPON1 − 37564 bp (NM_006108.1) 11  13,903,250 3.21 0.77 0.68 1.51 2.69 2.24 1.40 rs7935243 PHACS Intron3 (NM_032592.1) 11  44,050,992 3.13 0.80 0.72 1.53 2.67 2.95 2.11 rs562160 CHORDC1 − 291532 bp (NM_012124.1) 11  89,887,386 3.12 0.82 0.75 1.55 2.57 2.91 2.02 rs474530 DLG2 Intron1 (NM_001364.1) 11  83,930,298 3.02 0.95 0.91 2.00 2.56 ND ND rs493622 CHORDC1 − 286443 bp (NM_012124.1) 11  89,882,297 3.04 0.82 0.75 1.54 2.45 2.76 1.89 rs610160 GRIA4 Intron3 (NM_000829.1) 11 105,202,105 3.06 0.20 0.14 1.64 2.25 3.19 1.42 rs10844107 BICD1 − 37784 bp (NM_001714.1) 12  32,113,668 0.28 0.24 0.23 1.08 3.48 5.00 0.75 rs10862853 LOC387871 + 436103 bp (XM_373539) 12  83,274,707 1.19 0.82 0.78 1.28 3.34 3.97 4.53 rs979879 SLC6A15 + 353475 bp (NM_182767.2), 12  83,403,423 1.63 0.83 0.78 1.36 3.33 4.41 4.61 SLC6A15 + 375211 bp (NM_018057.3) rs11116400 SLC6A15 + 425437 bp (NM_182767.2), 12  83,331,461 1.53 0.83 0.78 1.34 3.33 4.38 4.65 SLC6A15 + 447173 bp (NM_018057.3) rs2611284 SLC6A15 + 335334 bp (NM_182767.2), 12  83,421,564 1.66 0.83 0.78 1.36 3.31 4.41 4.57 SLC6A15 + 357070 bp (NM_018057.3)

High- Risk High- Allele Risk Fre- Allele Odds Odds quency Fre- Critical Ratio Ratio Critical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs10746324 SLC6A15 + 349318 bp (NM_182767.2), 12  83,407,580 1.61 0.83 0.78 1.36 3.29 4.38 4.57 SLC6A15 + 371054 bp (NM_018057.3) rs11056970 LMO3 + 34143 bp (NM_0186403), 12  16,558,431 3.21 0.86 0.79 1.63 3.27 3.21 3.17 LMO3 + 34143 bp (NM_001001395.1) rs4766663 OAS1 + 7223 bp (NM_002534.1), 12 111,825,694 3.28 0.20 0.13 1.68 3.12 12.40 1.52 OAS1 + 5266 bp (NM_016816.1) rs7134411 FLJ25056 + 34943 bp (NM_182530.1) 12  68,673,713 0.33 0.51 0.49 1.08 3.12 1.17 0.61 rs1382851 FLJ36004 − 92384 bp (NM_152590.1) 12  25,689,829 2.11 0.58 0.51 1.33 3.10 1.86 2.07 rs7295295 LOC387871 + 418915 bp (XM_373539) 12  83,257,519 1.84 0.82 0.76 1.38 3.09 4.09 4.00 rs1380405 SLC6A15 + 351862 bp (NM_182767.2), 12  83,405,036 1.56 0.83 0.79 1.35 3.08 4.25 4.38 SLC6A15 + 373598 bp (NM_018057.3) rs11116414 SLC6A15 + 389377 bp (NM_182767.2), 12  83,367,521 1.46 0.83 0.79 1.33 3.07 4.21 4.42 SLC6A15 + 411113 bp (NM_018057.3) rs2468302 SLC6A15 + 354456 bp (NM_182767.2), 12  83,402,442 1.46 0.83 0.79 1.33 3.07 4.21 4.42 SLC6A15 + 376192 bp (NM_018057.3) rs2555255 LOC144742 + 11128 bp (XM_ 378388) 12 118,173,222 0.08 0.25 0.24 1.03 3.04 3.04 0.72 rs2072133 OAS3 Exon16 (NM_006187.2) 12 111,871,980 3.71 0.68 0.59 1.51 3.03 2.27 1.46 rs1647106 THRAP2 + 168009 bp (NM_015335.2) 12 114,691,094 3.67 0.33 0.24 1.56 3.02 2.29 1.63 rs10779090 LOC387871 + 423693 bp (XM_373539) 12  83,262,297 1.14 0.82 0.78 1.27 3.01 3.58 4.04 rs2125093 KLRA1 + 10392 bp (NM_006611.1) 12  10,622,647 3.52 0.77 0.68 1.54 2.92 2.11 1.27 rs900610 MGC50559 Intron2 (NM_173802.2) 12  31,707,890 3.14 0.16 0.10 1.75 2.91 1.47 1.98 rs10772350 STYK1 − 7029 bp (NM_018423.1) 12  10,724,935 3.08 0.71 0.62 1.47 2.83 1.91 1.11 rs4767030 OAS1 + 3826 bp (NM_002534.1), 12 111,822,297 3.40 0.21 0.14 1.68 2.81 3.49 1.66 OAS1 + 1869 bp (NM_016816.1) rs1647110 THRAP2 + 163373 bp (NM_015335.2) 12 114,695,730 3.37 0.29 0.21 1.56 2.76 2.29 1.62

High- Risk High- Allele Risk Fre- Allele Odds Odds Cri- quency Fre- Critical Ratio Ratio tical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs1859336 OAS3 − 8940 bp (NM_006187.2) 12 111,830,029 3.06 0.21 0.14 1.63 2.58 4.24 1.57 rs1700369 LOC441646 Intron8 (XM_497358) 12 126,367,113 3.00 0.95 0.90 1.97 2.55 1.54 0.71 rs7134391 OAS1 + 10940 bp (NM_002534.1), 12 111,829,411 3.09 0.20 0.14 1.63 2.50 3.57 1.57 OAS1 + 8983 bp (NM_016816.1) rs2270152 VWF Intron49 (NM_000552.2) 12   5,931,330 3.16 0.86 0.80 1.62 2.48 2.47 1.50 rs4767040 OAS3 − 2232 bp (NM_006187.2) 12 111,836,737 3.07 0.20 0.14 1.63 2.48 3.56 1.56 rs10774679 OAS3 − 1501 bp (NM_006187.2) 12 111,837,468 3.06 0.20 0.14 1.63 2.47 3.58 1.56 rs11104300 HGNT-JV-H − 287319 bp 12  86,022,432 3.05 0.21 0.15 1.61 2.44 3.37 1.52 (NM_013244.2) rs10735079 OAS3 Intron2 (NM_006187.2) 12 111,842,728 3.03 0.20 0.14 1.62 2.44 3.56 1.55 rs7961953 DKFZp762A217 Intron1 12  81,594,304 3.02 0.34 0.26 1.48 2.43 2.28 1.48 (NM_152588.1) rs261912 ETNK1 Intron6 (NM_018638.3) 12  22,728,208 3.01 0.85 0.78 1.58 2.43 3.04 2.02 rs4145280 G30 + 266246 bp (XM_498445) 13 104,643,159 0.25 0.51 0.50 1.06 3.95 1.12 0.55 rs4772238 CLYBL − 20285 bp (NM_206808.1), 13  99,202,794 0.14 0.12 0.11 1.06 3.78 0.00 1.53 CLYBL − 20285 bp (NM_138280.3) rs9519091 SLC10A2 − 518655 bp (NM_000452.1) 13 103,035,852 1.56 0.49 0.43 1.27 3.58 1.48 2.06 rs3916959 G30 + 269026 bp (XM_498445) 13 104,640,379 0.25 0.51 0.50 1.06 3.58 1.12 0.57 rs9558509 G30 + 271368 bp (XM_498445) 13 104,638,037 0.27 0.51 0.50 1.07 3.47 1.13 0.58 rs9300981 G30 + 469126 bp (XM_498445) 13 104,440,279 3.79 0.63 0.53 1.52 3.14 2.32 1.75 rs1606405 SLITRK1 + 664827 bp (NM_052910.1) 13  82,684,518 1.37 0.55 0.50 1.24 3.10 1.47 0.74 rs10492680 L0C400123 − 23647 bp (XM_378411) 13  39,702,836 3.01 0.93 0.88 1.83 2.46 6.22 3.50 rs7150435 ALKBH + 19861 bp (NM_006020.1) 14  77,189,287 0.00 0.53 0.53 1.00 3.42 1.09 1.92 rs759363 CHES1 Intron3 (NM_005197.1) 14  88,828,894 3.89 0.32 0.23 1.59 3.29 2.36 1.69 rs11159897 CHES1 Intron3 (NM_005197.1) 14  88,829,194 3.89 0.32 0.23 1.59 3.29 2.36 1.69 rs4902116 LOC401778 + 110022 bp (XM_377343) 14  61,774,890 2.61 0.57 0.49 1.38 3.12 1.93 1.98 rs2241127 CHES1 Intron2 (NM_005197.1) 14  88,892,969 1.47 0.31 0.26 1.29 3.11 0.99 1.80

High- Risk High- Allele Risk Fre- Allele Odds Odds quency Fre- Critical Ratio Ratio Critical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs10148022 LOC283584 − 265499 bp (XM_211108) 14  85,864,556 0.85 0.32 0.29 1.19 3.07 0.84 1.72 rs1571379 SEL1L − 289804 bp (NM_005065.3) 14  81,359,690 3.60 0.73 0.63 1.53 3.03 2.22 1.36 KCNK10 − 72402 bp (NM_138318.1), rs11622536 KCNK10 − 20310 bp (NM_138317.1), 14  87,879,410 0.64 0.77 0.75 1.16 3.00 0.64 0.38 KCNK10 −16406 bp (NM_021161.3) BRF1 Intron2 (NM_001519.2), rs2816632 BRF1 − 27133 bp (NM_145685.1), 14 104,812,400 3.27 0.21 0.14 1.64 2.78 4.49 1.36 BRF1 − 26587 bp (NM_145696.1) rs1106845 STELLAR + 19768 bp (XM_375075) 14  35,931,107 3.26 0.11 0.06 2.06 2.71 ND 1.98 rs17115925 SEL1L − 271331 bp (NM_005065.3) 14  81,341,217 3.00 0.72 0.64 1.46 2.39 2.22 1.56 rs7176242 ATP10A + 44699 bp (NM_024490.2) 15  23,428,814 0.19 0.85 0.85 1.07 3.26 0.09 0.06 rs16969520 C1B2Intron1 (NM_006383.2) 15  76,204,239 2.36 0.35 0.28 1.39 3.19 1.38 1.86 rs10902569 ADAMTS17 Intron3 (NM_139057.1) 15  98,663,829 0.08 0.67 0.67 1.03 3.10 0.64 0.41 rs11071129 UNC13C + 173927 bp (XM_496070) 15  52,882,022 0.20 0.59 0.58 1.05 3.08 1.37 2.11 rs1441354 FLJ13710 − 290691 bp (NM_024817.1) 15  69,517,251 0.22 0.25 0.24 1.07 3.07 5.71 0.78 rs11631211 ATP10A + 61309 bp (NM_024490.2) 15  23,412,204 0.22 0.86 0.85 1.08 3.06 0.10 0.07 rs12592527 UNC13C + 174082 bp (XM_496070) 15  52,882,177 0.27 0.60 0.58 1.07 3.05 1.42 2.13 rs4144951 FLJ38736 Intron17 (NM_182758.1) 15  51,643,802 3.40 0.16 0.09 1.82 2.73 2.80 1.87 rs2654216 EFTUD1 + 28186 bp (NM_024580.3) 15  80,181,440 3.18 0.60 0.51 1.44 2.57 2.14 1.54 rs8026133 SLCO3A1 − 26936 bp (NM_013272.2) 15  90,171,014 3.10 0.16 0.10 1.74 2.48 4.60 1.66 rs4780091 LOC440268 + 506 bp (XM_496063) 15  31,271,629 3.26 0.63 0.54 1.46 2.46 2.02 1.37 rs17191316 ANXA2 + 144537 bp (NM_004039.1) 15  58,282,291 3.23 0.07 0.03 2.61 2.37 ND 2.22 rs12597526 USP10 + 4263 bp (NM_005153.1) 16  83,374,937 1.28 0.38 0.33 1.24 3.91 2.51 0.81 rs2133803 LOC149329 − 13263 bp (XM_086494) 16  59,665,671 1.32 0.81 0.76 1.30 3.52 4.13 4.60 rs288601 CDH8 − 492870 bp (NM_001796.2) 16  61,120,407 1.81 0.53 0.47 1.30 3.35 1.61 0.77 rs1819829 FLJ31547 Intron9 (NM_145024.1) 16  54,444,785 2.53 0.79 0.73 1.46 3.32 4.58 3.80

High- Risk High- Allele Risk Fre- Allele Odds Odds quency Fre- Critical Ratio Ratio Critical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs2541639 HBZ + 531 bp (NM_005332.2) 16    145,035 2.77 0.22 0.16 1.55 3.13 1.23 1.90 rs372657 LOC283867 − 3128196p (XM_378606) 16 64,480,523 3.63 0.24 0.16 1.65 2.84 3.03 1.56 rs173840 LOC283867 − 313113 bp (XM_378606) 16 64,480,817 3.63 0.24 0.16 1.65 2.84 3.03 1.56 rs4843428 FOXL1 + 137429 bp (NM_005250.1) 16 85,308,297 3.20 0.88 0.81 1.66 2.75 1.89 1.05 rs254353 LOC283867 − 30150713p (XM_378606) 16 64,469,211 3.33 0.19 0.12 1.71 2.71 4.73 1.57 rs4077853 PLCG2 Intron27 (NM_002661.1) 16 80,528,471 3.16 0.35 0.27 1.49 2.62 2.17 1.57 rs3859079 CDH13 − 112144 bp (NM_001257.2) 16 81,105,935 3.17 0.66 0.58 1.46 2.51 2.17 1.60 rs8062968 LOC283867 − 298359 bp (XM_378606) 16 64,466,063 3.05 0.24 0.17 1.57 2.49 1.99 1.68 rs11074523 HS3ST2 Intron + (NM_006043.1) 16 22,734,434 3.11 0.80 0.73 1.53 2.48 2.40 1.56 WWOX − 1063753 bp (NM_130844.1), WWOX − 1063753 bp (NM_130791.1), rs8045067 WWOX − 1063753 bp (NM_016373.1), 16 77,754,805 3.35 0.75 0.67 1.52 2.43 2.17 1.49 WWOX − 1063753 bp (NM_018560.4), WWOX − 48197 bp (NM_130792.1) WWOX − 1063238 bp (NM_130844.1), WWOX − 1063238 bp (NM_130791.1), rs12443833 WWOX −1063238 bp (NM_016373.1), 16 77,754,290 3.17 0.72 0.63 1.48 2.38 2.11 1.45 WWOX − 1063238 bp (NM_018560.4), WWOX − 48712 bp (NM_130792.1) rs1877821 RGS9 − 9409 bp (NM_003835.1) 17 60,605,875 1.17 0.75 0.71 1.25 3.80 3.21 3.78 rs9896245 RGS9 − 11066 bp (NM_003835.1) 17 60,604,218 1.45 0.75 0.70 1.29 3.65 3.30 3.62 rs1029754 LOC401887 + 487202 bp (XM_497555) 17 66,236,699 2.11 0.89 0.84 1.51 3.62 0.23 0.12 rs17808998 NTN1 Intron2 (NM_004822.1) 17  8,919,071 2.23 0.63 0.56 1.35 3.30 1.57 0.81 rs9895463 SPACA3 − 6355 bp (NM_173847.2) 17 28,336,640 0.01 0.58 0.58 1.00 3.23 1.23 2.04 rs11868422 RPH3AL Intron1 (NM_006987.2) 17    198,072 3.62 0.21 0.14 1.71 3.05 2.06 1.85 rs1877823 RGS9 + 3031361 bp (NM_003835.1) 17 60,657,405 1.20 0.77 0.73 1.26 3.03 3.22 3.52

High- Risk High- Allele Risk Fre- Allele Odds Odds quency Fre- Critical Ratio Ratio Critical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) TRPV1 Exon11 (NM_080706.1), rs8065080 TRPV1 Exon12 (NM_080705.1), 17  3,427,196 3.67 0.69 0.60 1.51 2.88 2.25 1.51 TRPV1 Exon12 (NM_0187273), TRPV1 Exon13 (NM_080704.1) rs8082149 LOC342600 Intron2 (XM_292624) 17 51,927,894 3.52 0.92 0.86 1.85 2.66 3.49 1.99 rS2269459 POLR2A Intron22 (NM_000937.2) 17  7,353,762 3.11 0.79 0.72 1.52 2.51 2.46 1.63 rs2072255 KIAA0672 Intron10 (XM_375408) 17 12,793,117 3.09 0.21 0.14 1.63 2.43 3.35 1.53 rs9788983 RPH3AL Intron6 (NM_006987.2) 17    129,457 3.05 0.89 0.82 1.65 2.40 3.21 2.00 rs1879610 LOC441825 + 255198 bp (XM_497596) 18 73,469,750 1.98 0.95 0.91 1.72 3.48 0.26 0.11 rs11876045 LOC441816 − 222690 bp (XM_497584) 18 20,564,102 3.73 0.28 0.20 1.61 3.41 1.79 1.88 rs17070861 BCL2 Intron1 (NM_000633.1), 18 59,057,460 0.72 0.94 0.93 1.33 3.34 ND ND BCL2 + 786551 bp (NM_000657.1) rs1790870 CYB5 + 163 bp (NM_001914.1), 18 70,071,349 3.86 0.86 0.78 1.70 3.30 1.99 1.06 CYB5 + 163 bp (NM_148923.1) rs1790858 CYB5 Intron3 (NM_001914.1), 18 70,075,799 3.74 0.86 0.78 1.68 3.18 1.99 1.08 CYB5 Intron3 (NM_148923.1) rs17187933 LOC441816 − 214621 bp (XM_497584) 18 20,556,033 3.55 0.26 0.18 1.62 3.11 1.86 1.81 rs17088997 CYB5 + 3361 bp (NM_001914.1), 18 70,068,151 3.62 0.86 0.78 1.67 3.07 1.95 1.06 CYB5 + 3361 bp (NM_148923.1) rs1372481 LOC390856 Intron1 (XM_497590) 18 49,466,756 3.51 0.96 0.92 2.35 3.07 1.52 0.58 rs10468763 CLUL1 Intron5 (NM_014410.4), 18    622,239 0.40 0.22 0.21 1.12 3.06 0.50 1.61 CLUL1 Intron5 (NM_199167.1) rs3862680 DCC Intron1 (NM_005215.1) 18 48,184,338 3.65 0.60 0.50 1.49 2.97 2.24 1.56 rs3910695 LOC390856 Intron1 (XM_497590) 18 49,464,638 3.35 0.96 0.92 2.28 2.90 1.53 0.60 rs3862681 DCC Intron1 (NM_005215.1) 18 48,184,688 3.53 0.60 0.50 1.48 2.84 2.19 1.54 rs7238490 METTLA + 571947 bp (NM_022840.2) 18  1,955,583 3.40 0.71 0.62 1.49 2.72 2.04 1.27 rs9951036 LOC390856 Intron1 (XM_497590) 18 49,515,735 3.18 0.96 0.92 2.23 2.72 1.52 0.62

High- Risk High- Allele Risk Fre- Allele Odds Odds quency Fre- Critical Ratio Ratio Critical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs339858 LOC441816 − 124776 bp (XM_497584) 18 20,466,188 3.14 0.16 0.10 1.75 2.70 1.95 1.90 rs11151937 CYB5 + 4859 bp (NM_001914.1), 18 70,066,653 3.06 0.53 0.44 1.43 2.68 2.01 1.68 CYB5 + 4859 bp (NM_148923.1) rs8094863 LOC90855 Intron3 (XM_497589) 18 47,458,218 3.17 0.50 0.41 1.44 2.55 2.12 1.32 rs17260163 LOC441816 − 250775 bp (XM_497584) 18 20,592,187 3.13 0.29 0.21 1.53 2.54 2.21 1.59 rs8086430 LOC147468 + 250079 bp (XM_091809) 18 20,600,317 3.10 0.29 0.21 1.52 2.51 2.20 1.58 rs16940484 C18orf17 Intron6 (NM_153211.1) 18 19,936,298 3.09 0.34 0.26 1.49 2.51 2.02 1.58 rs7229080 LOC390856 Intron1 (XM_497590) 18 49,503,583 3.19 0.97 0.93 2.28 2.49 3.03 1.30 rs10502927 LOC390855 Intron3 (XM_497589) 18 47,502,071 3.01 0.49 0.41 1.43 2.45 2.09 1.27 rs17660384 ZNF175 − 10715 bp (NM_007147.2) 19 56,755,628 3.53 0.21 0.14 1.69 3.02 5.12 1.57 rs2864107 ZNF175 − 5504 bp (NM_007147.2) 19 56,760,839 3.40 0.21 0.14 1.68 2.90 4.82 1.58 rs1433083 FLJ12644 Exon5 (NM_023074.2) 19 57,085,796 3.14 0.95 0.91 2.07 2.66 ND ND rs6097745 BCAS1 Intron3 (NM_003657.1) 20 52,101,533 1.67 0.29 0.24 1.33 3.56 1.00 1.92 rs2870304 BCAS1 Intron3 (NM_003657.1) 20 52,106,624 1.74 0.30 0.25 1.33 3.49 1.06 1.91 rs8123014 C20orf23 + 571310 bp (NM_024704.3) 20 15,629,440 2.16 0.75 0.68 1.38 3.20 1.23 0.66 rs6115865 C20orf194 − 37687 bp (XM_045421) 20 3,307,303 3.63 0.38 0.29 1.52 2.87 2.29 1.52 rs7268851 C20orf17 Intron2 (NM_173485.2) 20 51,501,200 3.45 0.73 0.65 1.51 2.86 2.08 1.27 rs6134494 LOC440753 + 240718 bp (XM_498845) 20 12,196,345 3.12 0.22 0.15 1.61 2.86 1.59 1.86 rs3817879 PLCB1 Intron3 (NM_015192.2), 20  8,470,921 3.17 0.80 0.72 1.54 2.52 2.65 1.89 PLCB1 Intron3 (NM_182734.1) MATN4 Intron5 (NM_003833.2), rs2743246 MATN4 Intron4 (NM_030590.1), 20 43,362,112 3.10 0.88 0.88 1.64 2.43 2.97 1.85 MATN4 Intron3 (NM_030592.1) rs6014430 K1AA1755 Intron2 (XM_028810) 20 36,305,948 3.05 0.11 0.06 1.94 2.03 3.66 1.69 rs2154450 RUNX1 Intron5 (NM_001754.2) 21 35,141,436 0.85 0.44 0.40 1.18 3.94 1.14 2.01 rs4817695 RUNX1 Intron5 (NM_001754.2) 21 35,141,187 0.66 0.44 0.41 1.14 3.69 1.10 1.94 rs2825423 LOC388817 + 373452 bp (XM_371409) 21 19,526,124 3.31 0.26 0.19 1.58 2.64 3.09 1.38

High- Risk High- Allele Risk Fre- Allele Odds Odds quency Fre- Critical Ratio Ratio Critical in Glau- quency Odds Rate, (Homo- (Heter- Chro- rate, coma in Non- Ratio Geno- zygote) ozygote) mo- Physical Allele Patient Patient (Formula type (Formula (Formula dbSNP ID Exon, Intron some Location (-logP) Group Group 3) (-logP) 4) 5) rs4823324 E46L Intron10 (NM_013236.1) 22 44,558,660 3.69 0.51 0.41 1.49 3.04 2.26 1.32 NF2 Intron10 (NM_181825.1), NF2 Intron8 (NM_181831.1), NF2 Intron10 (NM_000268.2), NF2 Instron10 (NM_016418.4), NF2 Intron11 (NM_181826.1), NF2 Intron10 (NM_181827.1), rs2857648 NF2 Intron9 (NM_181828.1), 22 28,391,122 3.02 0.73 0.65 1.46 2.79 1.67 0.95 NF2 Intron9 (NM_181829.1), NF2 Intron8 (NM_181830.1), NF2 Intron10 (NM_181832.1), NF2 Intron4 (NM_181833.1), NF2 Intron5 (NM_181834.1), NF2 Intron8 (NM_181835.1) FBLN1 + 65094 bp (NM_006487.2), rs6006787 FBLN1 + 60443 bp (NM_001996.2), 22 44,340,222 3.31 0.50 0.40 1.46 2.72 2.22 1.38 FBLN1 + 58104 bp (NM_006485.2), FBLN1 + 22671 bp (NM_006486.2) rs572159 LOC284898 − 273642 bp (XM_379044) 22 26,054,663 3.11 0.94 0.89 1.92 2.48 4.67 2.44 rs467812 C22orf19 Intron2 (NM_003678.3) 22 28,265,503 3.22 0.27 0.19 1.56 2.48 2.23 1.57 rs5765558 E46L − 24767 bp (NM_013236.1) 22 44,363,516 3.05 0.58 0.49 1.43 2.34 2.01 1.37 rs6006179 C22orf19 Intron19 (NM_003678.3) 22 28,231,255 3.03 0.27 0.20 1.53 2.33 2.19 1.55

Tables 5 to 25 list dbSNP ID number or Affimetrix Array ID number for specifying known single nucleotide polymorphisms obtained, the exon, intron information (in a case where a single nucleotide polymorphism exists on a gene, the gene name and the exon or intron in which SNP exists are shown, and in a case where a single nucleotide polymorphism does not exist on a gene, neighboring genes and a distance between the gene and the single nucleotide polymorphism are shown), the chromosome number at which the single nucleotide polymorphism exists, the physical location of the single nucleotide polymorphism, the p-value for an allele according to a chi-square test (−log P), the high-risk allele frequencies in the glaucoma patient group and the non-patient group, the odds ratio for an allele, the p-value for a genotype according to a chi-square test (−log P), the odds ratio for a genotype of a homozygote, and the odds ratio for a genotype of a heterozygote. Here, in the tables, a portion of which odds ratio is indicated as ND shows a case where any one of the number of detection in the denominator is 0, so that the odds ratio could not be calculated.

According to the above studies, 413 single nucleotide polymorphisms of which alleles or genotypes were associated with glaucoma at a p-value of 1×10⁻³ or less were found.

When the allele or genotype frequencies listed in Tables 5 to 25 were compared between the non-patients without having family history and the glaucoma patients, a statistical difference was found. By determining an allele of any one of these single nucleotide polymorphisms, whether or not an allele that is identified in a higher frequency in the glaucoma patient group than that of the non-patient group exists in the sample can be determined.

Example 4 Comparison of Single Nucleotide Polymorphisms Between Progressive Glaucoma Cases and Nonprogressive Glaucoma Cases

The comparison on single nucleotide polymorphisms was made for progressive glaucoma cases and nonprogressive glaucoma cases in the same manner as in Example 3.

Concretely, blood donated under the consent on free will of the participants after having sufficiently explained the contents of studies from 210 cases of patients with progressive visual loss within a given time period, despite the treatments for lowering an intraocular pressure such as a drug for lowering an intraocular pressure or a surgical operation (progressive glaucoma cases), and 175 cases of patients without the progression (nonprogressive glaucoma cases), among the primary open-angle glaucoma patients and the normal tension glaucoma patients diagnosed on the basis of Guidelines offered by Japan Glaucoma Society, was used as a specimen, and alleles frequencies and genotypes frequencies between the groups were also compared by performing the analysis in the same manner as in Example 3. Alleles frequencies and genotype frequencies were statistically compared according to the chi-square test in the same manner. Single nucleotide polymorphisms of which alleles or genotypes show association with the progression of glaucoma at a p-value of 1×10⁻⁴ or less, i.e. −log P of 4 or more are listed in Tables 26 to 28. Here, the odds ratio for association of an allele with the progression of glaucoma, and the odds ratio for association of a genotype with the progression of glaucoma in each of the tables, respectively were calculated on the basis of the following formulas (6) to (8).

Odds Ratio for Allele=[(Number of Detection of an Allele Identified in High Frequency in Progressive Glaucoma Group, in Progressive Glaucoma Group)/(Number of Detection of an Allele Opposite to the Allele Identified in High Frequency in Progressive Glaucoma Group, in Progressive Glaucoma Group)]/[(Number of Detection of the Allele Identified in High Frequency in Progressive Glaucoma Group, in Nonprogressive Glaucoma Group)/(Number of Detection of the Allele Opposite to the Allele Identified in High Frequency in Progressive Glaucoma Group, in Nonprogressive Glaucoma Group)]  formula (6)

Odds Ratio for Genotype of Homozygote=[(Number of Detection of a Genotype Having Homozygote of an Allele Identified in High Frequency in Progressive Glaucoma Group, in Progressive Glaucoma Group)/(Number of Detection of a Genotypes Having Homozygote of an Allele Identified in High Frequency in Nonprogressive Glaucoma Group, in Progressive Glaucoma Group)]/[(Number of Detection of the Genotype Having Homozygote of the Allele Identified in High Frequency in Progressive Glaucoma Group, in Nonprogressive Glaucoma Group)/(Number of Detection of the Genotype Having Homozygote of the Allele Identified in High Frequency in Nonprogressive Glaucoma Group, in Nonprogressive Glaucoma Group)]  formula (7)

Odds Ratio for Genotype of Heterozygote=[(Number of Detection of a Genotype of Heterozygote in Progressive Glaucoma Group)/(Number of Detection of a Genotype Having Homozygote of an Allele Identified in High Frequency in Nonprogressive Glaucoma Group, in Progressive Glaucoma Group)]/[(Number of Detection of the Genotype of Heterozygote in Nonprogressive Glaucoma Group)/(Number of Detection of the Genotype Having Homozygote of the Allele Identified in High Frequency in Nonprogressive Glaucoma Group, in Nonprogressive Glaucoma Group)]  formula (8)

High-Risk High-Risk Allele Allele Frequency Frequency in Critical in Non- rate, Progressive progressive Allele1/ Chro- Physical Allele Glaucoma Glaucoma dbSNP ID Allele2 Exon, Intron mosome Location (-logP) Group Group rs11211059 A/G EIF2B3 Intron4 (NM_020365.1) 1  45,099,311 0.28 0.77 0.75 rs4927088 C/T SSBP3 Intron4 (NM_145716), 1  54,487,224 1.10 0.60 0.54 SSBP3 Intron4 (NM_018070.2) rs10172264 G/T LOC402072 + 152420 bp (XM_377741) 2  53,313,788 4.32 0.20 0.09 rs10460373 G/T UBE2E3 − 372131 bp (NM_182678.1), 2 181,298,487 3.24 0.82 0.72 UBE2E3 − 372361 bp (NM_006357.2) rs1520855 C/T FLJ12519 − 24239 bp (NM_032168.1) 2 190,107,426 1.13 0.65 0.59 rs1827101 C/T ITPR1 + 2326 bp (NM_002222.1) 3   4,866,407 1.36 0.75 0.69 rs4635691 C/G ITPR1 + 2783 bp (NM_002222.1) 3   4,866,864 1.24 0.75 0.69 rs9819062 A/C ITPR1 + 14847 bp (NM_002222.1) 3   4,878,928 1.41 0.75 0.68 rs12638937 G/T ITPR1 + 15316 bp (NM_002222.1) 3   4,879,397 1.32 0.75 0.69 rs3805345 A/G PAPSS1 Intron5 (NM_005443.4) 4 108,943,706 3.56 0.65 0.52 rs3805347 C/T PAPSS1 Intron5 (NM_005443.4) 4 108,959.666 3.70 0.67 0.53 rs17066530 A/G LOC285501 + 636489 bp (XM_209640) 4 179,923,545 4.60 0.92 0.81 rs405806 A/C LOC441062 + 175809 bp (XM_498994) 5  18,167,512 4.03 0.55 0.41 rs401889 A/G LOC441062 + 175873 bp (XM_498994) 5  18,167,576 4.60 0.53 0.38 rs4308461 A/C SV2C − 75087 bp (XM_403493) 5  75,339,908 4.03 0.79 0.66 rs2547455 C/T SV2C − 33137 bp (XM_043493) 5  75,381,858 4.40 0.80 0.67 rs2042974 C/G LHFPL2 − 11058 bp (NM_005779.1) 5  77,852,925 1.24 0.86 0.81 rs7719483 A/C LHFPL2 − 19056 bp (NM_005779.1) 5  77,860,923 0.88 0.86 0.82 rs17215893 C/T LHFPL2 − 20235 bp (NM_005779.1) 5  77,862,102 0.85 0.86 0.82 rs10045987 C/T LHFPL2 − 31149 bp (NM_005779.1) 5  77,873,016 0.88 0.86 0.82 rs11949567 A/G LHFPL2 − 35281 bp (NM_005779.1) 5  77,877,148 0.88 0.86 0.82 rs11950379 A/G LHFPL2 − 35775 bp (NM_005779.1) 5  77,877,642 0.79 0.85 0.82 rs6860516 A/G LHFPL2 − 35961 bp (NM_005779.1) 5  77,877,828 0.88 0.86 0.82 rs6881598 A/G LHFPL2 − 37710 bp (NM_005779.1) 5  77,879,577 0.88 0.86 0.82 Odds Odds Critical Ratio Ratio Odds rate, Homo- Hetero- Sequence Sequence High Risk Ratio Genotype zygote1) zygote) Containing Containing dbSNP ID Allele (Formula 6) (-logP) (Formula 7) (Formula 8) Allele 1 Allele 2 rs11211059 Allele 2 1.12 4.51 9.28 15.68 SEQ ID No: 81 SEQ ID No: 82 rs4927088 Allele 1 1.29 1.56 2.12 3.61 SEO ID No: 83 SEQ ID No: 84 rs10172264 Allele 1 2.43 3.91 2.54 2.85 SEQ ID No: 85 SEQ ID No: 86 rs10460373 Allele 1 1.81 4.16 1.42 0.54 SEQ ID No: 87 SEQ ID No: 88 rs1520855 Allele 1 1.31 4.67 2.51 4.22 SEQ ID No: 89 SEQ ID No: 90 rs1827101 Allele 2 1.39 4.66 0.73 0.29 SEQ ID No: 91 SEQ ID No: 92 rs4635691 Allele 1 1.36 4.25 0.76 0.31 SEQ ID No: 93 SEQ ID No: 94 rs9819062 Allele 1 1.39 4.23 0.81 0.33 SEQ ID No: 95 SEQ ID No: 96 rs12638937 Allele 1 1.38 4.03 0.80 0.33 SEQ ID No: 97 SEQ ID No: 98 rs3805345 Allele 2 1.73 4.10 2.57 0.94 SEQ ID No: 99 SEQ ID No: 100 rs3805347 Allele 2 1.77 4.07 2.92 1.09 SEQ ID No: 101 SEQ ID No: 102 rs17066530 Allele 1 2.62 4.15 4.56 1.55 SEQ ID No: 103 SEQ ID No: 104 rs405806 Allele 2 1.77 3.38 2.95 2.11 SEQ ID No: 105 SEQ ID No: 106 rs401889 Allele 2 1.86 4.14 3.23 2.37 SEQ ID No: 107 SEQ ID No: 108 rs4308461 Allele 1 1.89 3.12 3.36 1.81 SEQ ID No: 109 SEQ ID No: 110 rs2547455 Allele 1 1.97 3.63 3.03 1.39 SEQ ID No: 111 SEQ ID No: 112 rs2042974 Allele 2 1.47 4.37 ND ND SEQ ID No: 113 SEQ ID No: 114 rs7719483 Allele 2 1.34 5.18 ND ND SEQ ID No: 115 SEQ ID No: 116 rs17215893 Allele 1 1.34 5.14 ND ND SEQ ID No: 117 SEQ ID No: 118 rs10045987 Allele 2 1.34 5.18 ND ND SEQ ID No: 119 SEQ ID No: 120 rs11949567 Allele 2 1.34 5.18 ND ND SEQ ID No: 121 SEQ ID No: 122 rs11950379 Allele 2 1.31 4.97 ND ND SEQ ID No: 123 SEQ ID No: 124 rs6860516 Allele 1 1.34 5.18 ND ND SEQ ID No: 125 SEQ ID No: 126 rs6881598 Allele 2 1.34 5.18 ND ND SEQ ID No: 127 SEQ ID No: 128

High-Risk High-Risk Allele Allele Frequency Frequency in Critical in Non- Allele1/ Chro- Physical rate, Progressive progressive dbSNP ID Allele2 Exon, Intron mosome Location Allele Glaucoma Glaucoma rs6886783 C/T LHFPL2 − 37765 bp (NM_005779.1) 5  77,879,632 (-logP) Group Group rs6877525 C/T LHFPL2 − 38871 bp (NM_005779.1) 5  77,880,738 0.88 0.86 0.82 rs12697888 C/T LHFPL2 − 53535 bp (NM_005779.1) 5  77,895,402 0.88 0.86 0.82 rs1978629 C/T LHFPL2 − 56045 bp (NM_005779.1) 5  77,897,912 0.88 0.86 0.82 rs10076149 C/C LHFPL2 − 68743 bp (NM_005779.1) 5  77,910,610 0.88 0.86 0.82 rs730781 C/T LHFPL2 − 84106 bp (NM_005779.1) 5  77,925,973 0.85 0.86 0.82 rs9461154 C/T LRRC16 − 112934 bp (NM_0176402) 6  25,506,014 1.41 0.32 0.25 rs13193932 C/G ARHGAP18 Intron1 (NM_033515.2) 6 130,008,475 1.70 0.83 0.76 rs17070863 A/G LOC441173 + 172209 bp 6 141,772,290 4.46 0.55 0.40 (XM_496827) rs1877885 C/G LOC340268 Intron1 (XM_294634) 7   9,625,295 4.29 0.60 0.45 rs1913603 A/C LOC340268 Intron1 (XM_294634) 7   9,664,816 4.03 0.64 0.49 HDAC9 Intron21 (NM_058176.1), HDAC9 Intron21 (NM_178423.1), rs10230371 A/G HDAC9 Intron19 (NM_178425.1), 7  18,668,137 1.05 0.41 0.35 HDAC9 + 186432 bp (NM_014707.1), HDAC9 + 19615 bp (NM 058177.1) rs17152739 A/G LOC401384 + 201741 bp 7  78,935,541 4.66 0.78 0.64 (XM_379506) rs4316157 C/T LOC340357 Intron3 (XM_499106) 8  12,677,322 4.65 0.48 0.33 NRG1 − 233743 bp (NM_013958.1), NRG1 − 233775 bp (NM_013957.1), NRG1 − 233799 bp (NM_004495.1), NRG1 − 233842 bp (NM_013961.1), rs10503907 A/G NRG1 − 234103 bp (NM_013964.1), 8  32,291,552 4.11 0.92 0.83 NRG1 − 234127 bp (NM_013960.1), NRG1 − 234143 bp (NM_013956.1), NRG1 − 281336 bp (NM_013962.1), NRG1 − 332731 bp (NM_013959.1) Odds Odds Critical Ratio Ratio Odds rate, Homo- Hetero- Sequence Sequence High Risk Ratio Genotype zygote1) zygote) Containing Containing dbSNP ID Allele (Formula 6) (-logP) (Formula 7) (Formula 8) Allele 1 Allele 2 rs6886783 Allele 1.34 5.18 ND ND SEQ ID No: 129 SEQ ID No: 130 rs6877525 Allele 2 1.34 5.18 ND ND SEQ ID No: 131 SEQ ID No: 132 rs12697888 Allele 1 1.34 5.18 ND ND SEQ ID No: 133 SEQ ID No: 134 rs1978629 Allele 2 1.34 5.18 ND ND SEQ ID No: 135 SEQ ID No: 136 rs10076149 Allele 2 1.34 5.18 ND ND SEQ ID No: 137 SEQ ID No: 138 rs730781 Allele 1 1.34 5.09 ND ND SEQ ID No: 139 SEQ ID No: 140 rs9461154 Allele 2 1.39 4.01 11.34 0.85 SEQ ID No: 141 SEQ ID No: 142 rs13193932 Allele 2 1.52 4.30 22.83 26.08 SEQ ID No: 143 SEQ ID No: 144 rs17070863 Allele 2 1.86 3.61 3.42 1.72 SEQ ID No: 145 SEQ ID No: 146 rs1877885 Allele 2 1.80 3.67 3.45 2.04 SEQ ID No: 147 SEQ ID No: 148 rs1913603 Allele 2 1.79 3.75 3.85 2.37 SEQ ID No: 149 SEQ ID No: 150 rs10230371 Allele 1 1.29 4.38 1.11 2.63 SEQ ID No: 151 SEQ ID No: 152 rs17152739 Allele 2 1.98 3.78 3.43 1.65 SEQ ID No: 153 SEQ ID No: 154 rs4316157 Allele 2 1.89 3.65 3.29 1.88 SEQ ID No: 155 SEQ ID No: 156 rs10503907 Allele 1 2.46 3.27 8.80 3.83 SEQ ID No: 157 SEQ ID No: 158

High-Risk High-Risk Allele Allele Frequency Frequency in Critical in Non- Allele1/ Chro- Physical rate, Progressive progressive dbSNP ID Allele2 Exon, Intron mosome Location Allele Glaucoma Glaucoma rs9650336 C/T LOC286140 − 47376 bp 8  38,625,315 4.11 0.67 0.53 (XM_ 209913) rs1541082 A/C PIP5K1B Intron15 (NM_003558.1) 9  68,851,654 4.05 0.37 0.24 rs4979255 C/T LOC442430 − 505186p (XM_498339) 9 107,542,392 1.50 0.69 0.61 rs2395453 C/G KCNMA1 Intron18 (NM_002247.2) 10  78,411,565 1.77 0.60 0.51 rs2131216 A/T KCNMA1 Intron18 (NM_002247.2) 10  78,426,609 1.69 0.59 0.51 rs7112492 A/C LDHA − 10601 bp (NM_005566.1) 11  18,362,086 3.70 0.38 0.26 rs4755605 C/T LOC387761 − 170163 bp 11  42,404,449 3.08 0.57 0.45 (XM_373495) rs10892454 A/C LOC440070 + 32494 bp (XM_498530) 11 119,148,037 0.09 0.47 0.47 rs4269933 C/T LOC440370 + 38035 bp (XM_498530) 11 119,153,578 0.08 0.47 0.47 rs2322728 A/G FLJ40224 + 258937 bp 11 126,640,100 0.04 0.28 0.28 (NM_173579.1) rs4350423 A/G FLJ40126 Intron18 (NM_173599.1), 12  38,515,235 4.28 0.24 0.13 SLC2A13 Intron6 (NM_052885.1) rs10784314 C/T PPM1H Intron4 (XM_350880) 12  61,442,746 1.93 0.85 0.78 rs4408378 A/G LOC401725 + 252078 bp 12  82,300,515 4.01 0.82 0.70 (XM_377278) rs11059862 A/G DKFZp76102018 + 33295 bp 12 127,750,629 4.11 0.94 0.85 (XM_044062) rs17184839 A/G LOC440142 + 13577 bp (XM_495960) 13  59,763,528 4.07 0.14 0.05 rs7212115 G/T LOC400573 − 182083 bp 17  10,832,202 4.05 0.88 0.78 (XM_378649) rs295869 C/T LOC388375 + 71591 bp (XM_373726) 17  32,221,458 2.76 0.44 0.33 rs6045676 C/G PDYN + 18232 bp (NM_024411.2) 20   1,889,171 4.11 0.35 0.22 rs909882 A/G CHD6 Intron24 (NM_032221.3) 20  39,509,923 4.37 0.81 0.68 rs6017164 C/T C20orf65 − 26539 bp (NM_176791.2) 20  41,815,520 4.15 0.55 0.40 rs7275647 A/G NCAM2 Intron5 (NM_004540.2) 21  21,586,912 4.62 0.69 0.55 rs2837255 A/C PCP4 − 17259 bp (NM_006198.1) 21  40,143.991 4.33 0.70 0.56 Odds Odds Critical Ratio Ratio Odds rate, Homo- Hetero- Sequence Sequence High Risk Ratio Genotype zygote1) zygote) Containing Containing dbSNP ID Allele (Formula 6) (-logP) (Formula 7) (Formula 8) Allele 1 Allele 2 rs9650336 Allele 1 1.80 4.06 2.58 1.02 SEQ ID No: 159 SEQ ID No: 160 rs1541082 Allele 1 1.87 3.54 4.89 1.65 SEQ ID No: 161 SEQ ID No: 162 rs4979255 Allele 1 1.39 4.03 1.16 0.46 SEQ ID No: 163 SEQ ID No: 164 rs2395453 Allele 1 1.42 4.73 1.68 0.55 SEQ ID No: 165 SEQ ID No: 166 rs2131216 Allele 2 1.40 4.14 1.72 0.59 SEQ ID No: 167 SEQ ID No: 168 rs7112492 Allele 2 1.80 4.03 2.25 2.50 SEQ ID No: 169 SEQ ID No: 170 rs4755605 Allele 1 1.63 4.13 3.34 3.05 SEQ ID No: 171 SEQ ID No: 172 rs10892454 Allele 1 1.03 4.12 1.29 0.45 SEQ ID No: 173 SEQ ID No: 174 rs4269933 Allele 2 1.03 4.20 1.29 0.44 SEQ ID No: 175 SEQ ID No: 176 rs2322728 Allele 2 1.02 4.00 3.53 0.55 SEQ ID No: 177 SEQ ID No: 178 rs4350423 Allele 2 2.20 3.41 8.59 1.82 SEQ ID No: 179 SEQ ID No: 180 rs10784314 Allele 1 1.62 5.56 ND ND SEQ ID No: 181 SEQ ID No: 182 rs4408378 Allele 1 1.97 3.22 3.63 1.81 SEQ ID No: 183 SEQ ID No: 184 rs11059862 Allele 1 2.61 3.33 5.98 2.27 SEQ ID No: 185 SEQ ID No: 186 rs17184839 Allele 1 2.98 3.54 ND 3.09 SEQ ID No: 187 SEQ ID No: 188 rs7212115 Allele 2 2.17 2.12 2.65 1.55 SEQ ID No: 189 SEQ ID No: 190 rs295869 Allele 1 1.60 4.93 1.80 3.00 SEQ ID No: 191 SEQ ID No: 192 rs6045676 Allele 2 1.91 3.66 2.90 2.23 SEQ ID No: 193 SEQ ID No: 194 rs909882 Allele 1 2.01 3.58 4.37 2.25 SEQ ID No: 195 SEQ ID No: 196 rs6017164 Allele 2 1.80 3.44 3.33 1.62 SEQ ID No: 197 SEQ ID No: 198 rs7275647 Allele 1 1.89 3.98 3.18 1.43 SEQ ID No: 199 SEQ ID No: 200 rs2837255 Allele 1 1.86 3.37 3.28 1.82 SEQ ID No: 201 SEQ ID No: 202

Tables 26 to 28 list dbSNP ID number or Affimetrix Array ID number specifying known single nucleotide polymorphisms obtained, each of bases constituting Allele 1 and Allele 2, the exon, intron information (in a case where a single nucleotide polymorphism exists on a gene, the gene name and the exon or intron in which SNP exists are shown, and in a case where a single nucleotide polymorphism does not exist on a gene, neighboring genes and a distance between the gene and the single nucleotide polymorphism are shown), the chromosome number at which the single nucleotide polymorphism exists, the physical location of the single nucleotide polymorphism, the p-value for an allele according to a chi-square test (−log P), the high-risk allele frequencies in the progressive glaucoma group and the nonprogressive glaucoma group, the type of the high-risk allele (indicating whether the high-risk allele is Allele 1 or Allele 2), the odds ratio for an allele, the p-value for genotype according to a chi-square test (−log P), the odds ratio for a genotype of a homozygote, the odds ratio for a genotype of a heterozygote, and SEQ ID NO of the sequence containing Allele 1 and SEQ ID NO of the sequence containing Allele 2 in each of the polymorphic sites. Here, in the tables, a portion of which odds ratio is indicated as ND shows a case where any one of the number of detection in the denominator is 0, so that the odds ratio could not be calculated.

According to the above studies, 61 single nucleotide polymorphisms of which alleles or genotypes were associated with the progression of glaucoma at a p-value of 1×10⁻⁴ or less were found.

When the allele or genotype frequencies listed in Tables 26 to 28 were compared between the progressive glaucoma cases and the nonprogressive glaucoma cases, a statistical difference was found. By determining an allele of any one of these single nucleotide polymorphisms, whether or not an allele that is identified in a higher frequency in the progressive glaucoma group than that of the nonprogressive glaucoma group exists in the sample can be determined.

The allele or genotype identified in a high frequency in the progressive glaucoma group for a single nucleotide polymorphism listed in Tables 26 to 28 can be used as a marker showing that a progressive risk of glaucoma is high. On the other hand, an allele that is opposite to the allele or a genotype other than the genotype can be used as a marker showing that a progressive risk of glaucoma is low.

Also, a single nucleotide polymorphism of which allele or genotype shows association with the progression of glaucoma at a p-value of 1×10⁻³ or less, i.e. −log P of 3 or more, is listed in Tables 29 to 51.

High- High- Risk Risk Allele Allele Fre- Fre- Odds Odds quency quency Ratio Ratio Critical in Progres- in Non- Odds Critical (Homo- (Heter- Chro- rate, sive progressive Ratio rate, zygote) ozygote) mo- Physical Allele Glaucoma Glaucoma (Formula Genotype (Formula (Formula DBSNP_ID Exon, Intron some Location (-logP) Group Group 6) (-logP) 7) 8) rs1920146 FMO3 − 14117 bp 1 167,777,607 3.00 0.16 0.08 2.14 3.79 0.78 3.05 (NM_006894.3) rs594105 C8A Intron4 (NM_000562.1) 1  57,055,277 0.82 0.65 0.60 1.24 3.74 0.95 0.41 rs490647 GRIK3 + 23871 bp 1  36,911,836 3.13 0.39 0.28 1.69 3.43 1.92 2.39 (NM_000831.2) rs10489624 C8A Intron6 (NM_000562.1) 1  57,061,635 0.83 0.65 0.60 1.24 3.39 1.00 0.44 rs11117962 LOC128153 + 9779 bp 1 214,438,658 1.33 0.60 0.53 1.34 3.32 1.49 0.60 (NM_138796.2) rs868162 NPHP Intron22 (NM_015102.2) 1   5,868,502 0.74 0.76 0.72 1.25 3.32 0.41 0.21 rs525798 GRIK3 + 25728 bp 1  36,909,979 3.12 0.40 0.28 1.68 3.28 1.97 2.33 (NM_000831.2) rs11120300 SMYD2 Intron11 1 210,897,894 1.38 0.08 0.04 1.90 3.14 0.23 4.08 (NM_020197.1) rs10494300 KCNN3 Intron3 1 151,539,619 3.13 0.61 0.49 1.64 3.14 2.56 1.09 (NM_170782.1), KCNN3 Intron3 (NM_002249.3) rs17401966 KIF1B Intron24 1  10,319,737 2.53 0.28 0.19 1.68 3.09 17.83 1.28 (NM_015074.2), KIF1B + 18633 bp (NM_183416.2) rs687328 GADD45A − 40088 bp 1  67,822,816 3.19 0.75 0.63 1.71 3.07 3.66 3.07 (NM_001924.2) rs7517439 EIF2B3 + 3647 bp 1  44,981,960 0.01 0.75 0.75 1.01 3.05 4.99 7.80 (NM_020365.1) rs479714 GRIK3 + 26576 bp 1  36,909,131 2.84 0.39 0.28 1.64 3.01 1.86 2.26 (NM_000831.2) rs7528341 GRIK3 + 125440 bp 1  36,810,267 3.27 0.75 0.63 1.73 2.97 2.40 1.14 (NM_000831.2) rs1339411 KCNK2 + 61589 bp 1 211,859,142 3.20 0.33 0.22 1.76 2.91 2.53 2.08 (NM_014217.1) rs947130 LOC391075 − 11088 bp 1 119,728,774 3.47 0.82 0.71 1.86 2.89 4.69 2.75 (XM_497702) rs7534078 SYT2 Intron1 (NM_177402.3) 1 199,346,710 3.84 0.37 0.25 1.84 2.89 2.83 1.87 rs479779 GRIK3 + 10551 bp 1  36,925,156 3.03 0.39 0.28 1.67 2.86 2.00 2.16 (NM_000831.2) rs2993076 GRIK3 + 5529 bp 1  36,930,178 3.00 0.36 0.25 1.69 2.84 2.00 2.15 (NM_000831.2) rs11590929 LMO4 + 403174 bp 1  87,926,458 3.65 0.96 0.89 2.98 2.83 4.15 1.35 (NM_006769.2) rs1416658 KCNK2 + 6613 bp 1 211,804,166 3.28 0.32 0.21 1.79 2.82 2.63 2.02 (NM_014217.1) rs4652921 GRIK3 + 91841 bp 1  36,843,866 3.22 0.66 0.54 1.67 2.81 2.56 1.25 (NM_000831.2) rs10157596 SLC35F3 − 17535 bp 1 230,329,879 3.29 0.71 0.59 1.71 2.80 3.48 2.28 (NM_173508.1) rs1416659 KCNK2 + 6647 bp 1 211,804,200 3.17 0.31 0.21 1.77 2.79 2.48 2.04 (NM_014217.1)

High- High- Risk Risk Allele Allele Fre- Fre- Odds Odds quency quency Ratio Ratio Critical in Progres- in Non - Odds Critical (Homo- (Heter- Chro- rate, sive progressive Ratio rate, zygote) ozygote) mo- Physical Allele Glaucoma Glaucoma (Formula Genotype (Formula (Formula DBSNP_ID Exon, Intron some Location (-logP) Group Group 6) (-logP) 7) 8) rs11120527 KCNK2 Intron6 1 211,796,452 3.16 0.32 0.21 1.77 2.79 2.49 2.05 (NM_014217.1) rs10494994 KCNK2 Intron5 1 211,750,602 3.50 0.26 0.16 1.93 2.76 3.29 1.97 (NM_014217.1) rs6665581 VAMP4 − 9932 bp 1 168,452,803 3.09 0.39 0.27 1.69 2.72 3.73 1.38 (NM_201994.1), VAMP4 − 9932 bp (NM_003762.2) rs12120152 VA MP4 − 12595 bp 1 168,455,466 3.09 0.39 0.27 1.69 2.72 3.73 1.38 (NM_201994.1), VAMP4 − 12595 bp (NM_003762.2) rs2293325 CD3Z Intron1 1 164,157,804 3.18 0.78 0.67 1.74 2.69 2.74 1.41 (NM_000734.2), CD3Z Intron1 (NM_198053.1) rs6577539 CA6 − 16705 bp 1   8,923,501 3.16 0.94 0.87 2.40 2.69 ND ND (NM_001215.1) rs34305923 GRIK3 + 122474 bp 1  36,813,233 3.10 0.74 0.62 1.69 2.66 2.43 1.23 (NM_000831.2) rs1315219 FLJ23129 Intron7 1  67,031,546 3.32 0.58 0.45 1.67 2.63 2.78 1.54 (NM_024763.3), FLJ123129 Intron7 (NM_207014.1) rs10798603 VAMP4 Intron4 1 168,412,039 3.37 0.36 0.24 1.77 2.60 3.30 1.65 (NM_201994.1), VAMP4 Intron4 (NM_003762.2) rs1317252 TDE2L Intron2 1  31,566,351 3.25 0.91 0.82 2.10 2.51 4.36 2.10 (NM_178865.2) rs12024194 VAMP4 − 12277 bp 1 168,455,148 3.21 0.22 0.13 1.95 2.44 4.16 1.86 (NM_201994.1), VAMP4 − 12277 bp (NM_003762.2) rs10489250 VAMP4 − 4860 bp 1 168,447,731 3.03 0.22 0.13 1.91 2.28 3.12 1.91 (NM_201994.1), VAMP4 − 4860 bp (NM_003762.2) rs271351 LOC391025 − 173869 bp 1  29,821,213 3.21 0.16 0.08 2.22 2.23 4.90 1.96 (XM_372775) rs6689380 LOC339535 − 409013 bp 1 235,384,371 3.08 0.97 0.92 3.08 2.17 ND ND (XM_378941) rs9943293 VAMP4 + 14337 bp 1 168,386,625 3.03 0.34 0.23 1.71 2.16 2.67 1.65 (NM_201994.1), VAMP4 + 18093 bp (NM_003762.2) rs4342884 VAMP4 Intron4 1 168,416,489 3.03 0.36 0.25 1.72 2.11 2.81 1.52 (NM_201994.1), VAMP4 Intron4 (NM_003762.2) rs11691504 UBE2E3 − 377923 bp 2 181,292,695 3.11 0.82 0.72 1.79 3.96 1.41 0.55 (NM_182678.1), UBE2E3 − 378153 bp (NM_006357.2)

High- High- Risk Risk Allele Allele Fre- Fre- Odds Odds Cri- quency quency Critical Ratio Ratio tical in Progres- in Non - Odds rate, (Homo- (Heter- Chro- rate, sive progressive Ratio Geno- zygote) ozygote) mo- Physical Allele Glaucoma Glaucoma (Formula type (Formula (Formula DBSNP_ID Exon, Intron some Location (-logP) Group Group 6) (-logP) 7) 8) rs9679229 UBE2E3 −350430 bp 2 181,320,188 3.05 0.82 0.72 1.77 3.90 1.41 0.55 (NM_182678.1), UBE2E3 −350660 bp (NM_006357.2) rs11691031 C2orf29 − 90020 bp 2 101,237,876 1.36 0.49 0.42 1.34 3.85 1.62 2.75 (NM_017546.3) rs714545 UBE2E3 − 463121 bp 2 181,207,497 3.54 0.81 0.70 1.85 3.76 1.88 0.76 (NM_182678.1), UBE2E3 − 463351 bp (NM_006357.2) rs10931418 FLJ12519 − 41174 bp 2 190,090,541 0.90 0.65 0.59 1.26 3.61 2.14 3.40 (NM_032168.1) rs4667078 UBE2E3 − 367916 bp 2 181,302,702 2.87 0.81 0.72 1.74 3.57 1.42 0.58 (NM_182678.1), UBE2E3 − 368146 bp (NM_006357.2) rs1355216 SCN7A − 183021 bp 2 167,352,006 3.14 0.86 0.77 1.91 3.55 1.25 0.50 (NM_002976.1) rs11695159 FLJ12519 − 22944 bp 2 190,108,721 0.79 0.64 0.59 1.23 3.47 2.07 3.32 (NM_032168.1) rs13032853 FLJ12519 Intron1 2 190,134,918 1.05 0.65 0.59 1.29 3.45 2.20 3.33 (NM_032168.1) rs733830 C2orf29 − 91059 bp 2 101,236,837 1.54 0.49 0.41 1.38 3.31 1.73 2.57 (NM_017546.3) rs16833004 GLS − 41329 bp 2 191,529,780 2.52 0.97 0.92 2.77 3.29 1.02 0.15 (NM_014905.2) rs11563200 TRPM8 Intron25 2 234,706,809 0.01 0.58 0.57 1.01 3.27 0.70 0.35 (NM_0240803) rs10930240 SCN7A − 162624 bp 2 167,331,609 2.96 0.87 0.78 1.86 3.25 1.26 0.53 (NM_002976.1) rs9287871 SCN7A − 162839 bp 2 167,331,824 2.96 0.87 0.78 1.86 3.25 1.26 0.53 (NM_002976.1) rs16860887 LOC91526 Intron15 2 197,723,413 3.53 0.90 0.81 2.15 3.23 2.07 0.82 (NM_153697.1) rs1840111 UBE2E3 − 484947 bp 2 181,185,671 3.05 0.77 0.66 1.71 3.22 1.84 0.79 (NM_182678.1), UBE2E3 − 485177 bp (NM_006357.2) rs934706 NXPH2 − 373561 bp 2 139,745,104 1.84 0.21 0.15 1.60 3.22 ND 0.99 (XM_371573) rs7420360 EPHA4 + 369107 bp 2 221,739,147 0.50 0.41 0.38 1.16 3.21 0.93 2.18 (NM 004438.3) rs6739369 FLJ20701 Intron3 2 229,738,357 3.71 0.18 0.08 2.39 3.20 4.06 2.60 (NM_017933.3) rs4850410 LOC91526 Intron15 2 197,745,675 3.81 0.93 0.84 2.40 3.20 2.97 1.13 (NM_153697.1) rs1453054 UBE2E3 − 485205 bp 2 181,185,413 3.18 0.78 0.67 1.75 3.13 2.03 0.90 (NM_182678.1), UBE2E3 − 485435 bp (NM_006357.2)

High- High- Risk Risk Allele Allele Fre- Fre- Odds Odds Cri- quency quency Critical Ratio Ratio tical in Progres- in Non - Odds rate, (Homo- (Heter- Chro- rate, sive progressive Ratio Geno- zygote) ozygote) mo- Physical Allele Glaucoma Glaucoma (Formula type (Formula (Formula DBSNP_ID Exon, Intron some Location (-logP) Group Group 6) (-logP) 7) 8) rs10186570 UBE2E3 − 482951 bp 2 181,187,667 2.67 0.78 0.68 1.65 3.08 1.62 0.71 (NM_182678.1), UBE2E3 − 483181 bp (NM_006357.2) rs4076919 FLJ10116 + 86710 bp 2 216,546,324 3.09 0.83 0.73 1.80 3.07 1.92 0.86 (NM_018000.1) rs968871 FLJ32955 + 20953 bp 2 150,428,575 3.81 0.45 0.31 1.77 3.06 3.17 1.75 (NM_153041.1) rs968873 FLJ32955 + 20796 bp 2 150,428,732 3.81 0.45 0.31 1.77 3.06 3.17 1.75 (NM_153041.1) rs13426748 LOC91526 Intron15 2 197,723,066 3.39 0.90 0.81 2.11 3.06 2.01 0.82 (NM_153697.1) rs2564118 FLJ32312 Intron4 2 61,144,940 1.22 0.52 0.45 1.32 3.06 1.97 0.70 (NM_144709.1) rs1468981 KLF7 + 36314 bp 2 207,734,721 0.36 0.59 0.56 1.12 3.04 0.99 0.46 (NM_003709.1) rs1641385 FLJ32955 + 20086 bp 2 150,429,442 3.71 0.45 0.32 1.75 2.97 3.13 1.73 (NM_153041.1) rs16825626 FLJ20701 Intron3 2 229,744,146 3.38 0.17 0.08 2.27 2.94 3.11 2.51 (NM_017933.3) rs4261668 MYL1 Intron3 2 210,987,818 3.62 0.35 0.23 1.81 2.91 3.39 1.81 (NM_079422.1), MYL1 Intron3 (NM_079420.1) rs848241 FLJ32955 Intron3 2 150,460,159 3.55 0.43 0.31 1.73 2.87 3.02 1.78 (NM_153041.1) rs1196155 PPP1R1C Intron2 (XM_087137) 2 182,746,778 3.43 0.68 0.55 1.71 2.87 3.23 2.15 rs1104870 ALK Intron15 (NM_004304.3) 2 29,366,069 3.60 0.17 0.08 2.36 2.85 6.13 2.33 rs12692654 KCNH7 Intron2 2 163,309,182 3.36 0.77 0.65 1.76 2.83 2.82 1.44 (NM_033272.2), KCNH7 Intron2 (NM_173162.1) rs4667333 FLJ32955 Intron3 2 150,461,734 3.44 0.44 0.31 1.72 2.78 3.00 1.77 (NM_153041.1) rs787433 LOC401014 + 29562 bp 2 145,697,590 3.44 0.42 0.30 1.72 2.78 3.29 1.54 (XM_379141) rs1196185 PPP1R1C Intron2 (XM_087137) 2 182,710,465 3.33 0.67 0.55 1.68 2.78 3.08 2.11 rs10496018 LOC402072 + 151618 bp 2  53,312,986 3.28 0.16 0.07 2.29 2.72 2.53 2.53 (XM_377741) rs7582411 LOC91526 Intron1 2 197,738,392 3.10 0.91 0.83 2.13 2.71 2.16 0.89 (NM_153697.1) rs1529404 MYCN + 99328 bp 2  16,137,052 3.29 0.88 0.79 1.98 2.67 6.63 3.70 (NM_005378.3) rs1608976 FLJ32955 Intron3 2 150,460,868 3.20 0.44 0.31 1.70 2.67 3.00 1.81 (NM_153041.1) rs2701664 PPP1R1C Intron2 (XM_087137) 2 182,734,170 3.22 0.67 0.55 1.66 2.61 2.94 2.00 rs1196160 PPP1R1C Intron3 (XM_087137) 2 182,753,518 3.22 0.67 0.55 1.66 2.61 2.94 2.00

TABLE 33 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs1358105 FLJ32955 +17818 bp (NM_153041.1) 2 150,431,710 3.30 0.39 rs1724855 FLJ32955 Intron3 (NM_153041.1) 2 150,455,469 3.22 0.43 rs17589066 DNAH7 Intron48 (NM_018897.1) 2 196,522,530 3.05 0.83 rs31276 FLJ20701 Intron3 (NM_017933.3) 2 229,746,025 3.08 0.19 rs7569506 FLJ39822 +44702 bp (NM_173512.1) 2 165,535,617 3.15 0.85 rs16838454 KIAA1679 Intron9 (XM_046570) 2 137,843,162 3.08 0.16 rs17041614 ITPR1 +16975 bp (NM_002222.1) 3 4,881,056 1.28 0.75 rs784288 MDS1 Intron2 (NM_004991.1) 3 170,453,933 3.72 0.79 rs6773050 CDGAP Intron10 (XM_291085) 3 120,606,504 2.34 0.64 rs6792308 ITPR1 +11521 bp (NM_002222.1) 3 4,875,602 1.14 0.73 rs1828652 PLSCR4 Intron6 (NM_020353.1) 3 147,397,711 3.96 0.47 rs1877268 LOC93556 +73662 bp (XM_376284) 3 170,104,751 2.31 0.37 rs16852789 LOC93556 +75467 bp (XM_376284) 3 170,106,556 2.31 0.37 rs11920980 LOC440985 −77863 bp (XM_498948) 3 154,176,162 1.13 0.57 rs7429749 FTHFD Intron1 (NM_012190.2), 3 127,371,520 2.65 0.21 FTHFD Intron1 (NM_144776.1) rs7624272 SEMA5B Intron1 (NM_018987.1) 3 124,178,241 3.01 0.10 rs6763643 MYRIP Intron3 (NM_015460.1) 3 40,072,995 0.70 0.38 rs4685335 RAFTLIN Intron4 (NM_015150.1) 3 16,423,640 0.62 0.47 rs12490570 LOC152118 −107632 bp (XM_098163) 3 154,577,350 3.96 0.92 rs7371987 CCR3 +10346 bp (NM_001837.2), 3 46,293,512 3.21 0.31 CCR3 +10346 bp (NM_178329.1) rs3957816 PCCB −13296 bp (NM_000532.2) 3 137,438,550 3.71 0.25 rs9839623 CCR3 +15697 bp (NM_001837.2), 3 46,298,863 3.07 0.31 CCR3 +15697 bp (NM_178329.1) rs17016781 RARB Intron3 (NM_000965.2), 3 25,580,890 3.62 0.65 RARB Intron3 (NM_016152.2) High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs1358105 0.27 1.72 2.59 3.20 1.60 rs1724855 0.31 1.68 2.56 2.86 1.72 rs17589066 0.72 1.82 2.53 4.89 2.95 rs31276 0.11 2.02 2.53 6.18 2.03 rs7569506 0.76 1.87 2.53 3.48 1.81 rs16838454 0.08 2.23 1.70 2.79 1.93 rs17041614 0.69 1.37 3.98 0.79 0.33 rs784288 0.67 1.85 3.79 7.54 4.94 rs6773050 0.53 1.53 3.56 2.99 3.29 rs6792308 0.67 1.33 3.52 0.83 0.37 rs1828652 0.34 1.78 3.49 2.66 2.23 rs1877268 0.27 1.55 3.41 1.49 2.45 rs16852789 0.27 1.55 3.41 1.49 2.45 rs11920980 0.50 1.30 3.36 1.54 0.59 rs7429749 0.13 1.85 3.23 ND 2.16 rs7624272 0.04 2.83 3.22 ND 3.06 rs6763643 0.34 1.22 3.17 2.51 0.67 rs4685335 0.43 1.19 3.15 1.22 2.39 rs12490570 0.82 2.35 3.05 5.13 2.26 rs7371987 0.20 1.78 3.02 6.91 1.56 rs3957816 0.14 2.01 2.97 5.03 1.91 rs9839623 0.21 1.76 2.91 6.79 1.53 rs17016781 0.51 1.72 2.88 2.77 1.46

TABLE 34 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs453570 CISH +6457 bp (NM_013324.4), 3 50,612,473 3.25 0.67 CISH +6457 bp (NM_145071.1) rs13096142 CCR3 −1944 bp (NM_001837.2), 3 46,256,748 3.04 0.35 CCR3 −1944 bp (NM_178329.1) rs696518 STAG1 Intron21 (NM_005862.1) 3 137,602,998 3.63 0.28 rs6446245 DOCK3 Intron5 (NM_004947.2) 3 51,012,298 3.15 0.66 rs16833788 SEMA5B −6558 bp (NM_018987.1) 3 124,236,700 3.37 0.10 rs6440881 LOC152118 −56902 bp (XM_098163) 3 154,628,080 3.51 0.90 rs10510568 RARB Intron3 (NM_000965.2), 3 25,577,736 3.24 0.64 RARB Intron3 (NM_016152.2) rs16833786 SEMA5B −5978 bp (NM_018987.1) 3 124,236,120 3.26 0.10 rs1545105 LOC389100 +81379 bp (XM_374035) 3 29,199,691 3.01 0.37 rs9883170 LOC389100 +82213 bp (XM_374035) 3 29,198,857 3.04 0.37 rs17016778 RARB Intron3 (NM_000965.2), 3 25,580,286 3.28 0.64 RARB Intron3 (NM_016152.2) rs2174746 LOC152118 −103841 bp (XM_098163) 3 154,581,141 3.52 0.92 rs11712746 KCNMB2 −262329 bp (NM_181361.1), 3 179,474,597 3.12 0.25 KCNMB2 −284723 bp (NM_005832.3) rs684773 PCCB −12843 bp (NM_000532.2) 3 137,439,003 3.26 0.22 rs695983 STAG1 Intron29 (NM_005862.1) 3 137,547,245 3.33 0.24 rs1154988 LOC391581 −434 bp (XM_497940) 3 137,407,889 3.23 0.23 rs2232248 HEMK1 Exon3 (NM_016173.1) 3 50,584,628 3.11 0.66 rs696081 PCCB Intron13 (NM_000532.2) 3 137,529,887 3.21 0.26 rs2140450 PPP2R3A Intron5 (NM_002718.3), 3 137,252,444 3.01 0.33 PPP2R3A Intron4 (NM_181897.1) High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs453570 0.55 1.68 2.88 3.30 1.85 rs13096142 0.24 1.71 2.87 4.85 1.39 rs696518 0.16 1.94 2.87 4.86 1.74 rs6446245 0.54 1.65 2.80 3.11 2.26 rs16833788 0.03 3.22 2.78 ND 3.29 rs6440881 0.80 2.10 2.74 6.57 3.53 rs10510568 0.52 1.67 2.70 2.90 1.58 rs16833786 0.03 3.16 2.68 ND 3.23 rs1545105 0.26 1.68 2.67 2.20 2.04 rs9883170 0.26 1.69 2.64 2.26 2.00 rs17016778 0.52 1.67 2.61 2.73 1.53 rs2174746 0.83 2.26 2.61 5.02 2.39 rs11712746 0.15 1.87 2.60 6.36 1.74 rs684773 0.13 1.98 2.58 5.71 1.84 rs695983 0.14 1.94 2.58 5.20 1.72 rs1154988 0.13 1.98 2.55 5.68 1.85 rs2232248 0.55 1.65 2.55 2.94 1.85 rs696081 0.16 1.86 2.49 4.24 1.72 rs2140450 0.23 1.72 2.47 3.87 1.50

TABLE 35 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs6440874 LOC152118 −101011 bp (XM_098163) 3 154,583,971 3.33 0.92 rs9852831 LOC152118 −133737 bp (XM_098163) 3 154,551,245 3.19 0.90 rs9822326 LOC339894 Intron2 (XM_379230) 3 158,286,267 3.17 0.54 rs548288 PCCB Intron1 (NM_000532.2) 3 137,452,453 3.09 0.23 rs7428299 EDEM1 +469242 bp (XM_376201) 3 5,705,884 3.02 0.68 rs12648912 PAPSS1 +17033 bp (NM_005443.4) 4 108,875,394 3.91 0.64 rs1865328 LYAR +1510 bp (NM_017816.1) 4 4,386,001 0.23 0.50 rs531823 QDPR +272295 bp (NM_000320.1) 4 16,891,997 3.28 0.64 rs2642849 UGT2B4 +7559 bp (NM_021139.1) 4 70,519,085 3.18 0.55 rs2736463 UGT2B4 +17920 bp (NM_021139.1) 4 70,508,724 3.08 0.55 rs11734419 MAML3 Intron2 (NM_018717.2) 4 141,040,368 3.22 0.46 rs12502059 PAPSS1 Intron4 (NM_005443.4) 4 108,962,816 3.03 0.61 rs4697446 DHX15 +259479 bp (NM_001358.1) 4 23,945,891 3.30 0.38 rs7692155 KIAA1109 −44906 bp (XM_371706) 4 123,386,649 3.06 0.72 rs17605639 LOC389204 −297625 bp (XM_374079) 4 27,290,099 3.09 0.80 rs584374 PPARGC1A −165848 bp (NM_013261.2) 4 23,733,817 3.55 0.11 rs17134333 EPB41L4A Intron2 (NM_022140.2) 5 111,670,626 2.67 0.71 rs7718321 EPB41L4A Intron1 (NM_022140.2) 5 111,697,251 0.93 0.69 rs7712363 LOC389319 −181104 bp (XM_374134) 5 125,542,548 1.03 0.76 rs10076364 LOC389319 −212764 bp (XM_374134) 5 125,510,888 0.93 0.75 rs7703461 SV2C Intron3 (XM_043493) 5 75,529,168 3.78 0.40 rs194229 MGC10067 −22589 bp (NM_145049.1) 5 158,600,287 1.24 0.50 rs10478702 LOC389319 −173069 bp (XM_374134) 5 125,550,583 1.04 0.76 rs17134365 EPB41L4A Intron1 (NM_022140.2) 5 111,694,455 1.04 0.72 rs11743891 FSTL4 Intron3 (XM_048786) 5 132,838,807 0.29 0.42 rs166296 SEMA6A Intron3 (NM_020796.2) 5 115,861,466 3.48 0.38 rs17731499 KIBRA Intron1 (NM_015238.1) 5 167,697,178 3.53 0.25 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs6440874 0.83 2.21 2.45 4.99 2.44 rs9852831 0.82 2.08 2.43 5.05 2.57 rs9822326 0.42 1.64 2.41 2.56 1.39 rs548288 0.13 1.91 2.34 4.47 1.76 rs7428299 0.56 1.64 2.27 2.67 1.81 rs12648912 0.51 1.76 3.67 2.92 1.24 rs1865328 0.48 1.08 3.41 1.21 0.48 rs531823 0.51 1.67 2.94 1.78 0.67 rs2642849 0.43 1.64 2.90 2.77 2.13 rs2736463 0.43 1.63 2.86 2.72 2.15 rs11734419 0.34 1.67 2.79 2.64 1.96 rs12502059 0.49 1.64 2.75 2.62 1.22 rs4697446 0.26 1.73 2.67 3.40 1.64 rs7692155 0.61 1.67 2.60 3.39 2.28 rs17605639 0.70 1.76 2.50 3.93 2.53 rs584374 0.04 3.20 1.90 5.93 1.94 rs17134333 0.60 1.63 3.71 1.80 0.69 rs7718321 0.64 1.27 3.38 0.94 0.42 rs7712363 0.71 1.32 3.38 0.59 0.28 rs10076364 0.70 1.29 3.27 0.67 0.32 rs7703461 0.27 1.80 3.27 3.99 1.35 rs194229 0.43 1.32 3.20 1.57 2.53 rs10478702 0.70 1.32 3.19 0.71 0.33 rs17134365 0.66 1.30 3.12 0.92 0.42 rs11743891 0.40 1.10 3.11 1.75 0.58 rs166296 0.26 1.76 3.07 4.18 1.40 rs17731499 0.14 1.97 3.04 9.22 1.51

TABLE 36 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs2055375 LOC441075 +72079 bp (XM_499000) 5 60,566,977 3.56 0.26 rs1560026 LOC389319 −225968 bp (XM_374134) 5 125,497,684 0.82 0.74 rs16869864 PTGER4 −300343 bp (NM_000958.2) 5 40,415,446 3.36 0.21 rs7736074 SLC6A19 −12310 bp (XM_291120) 5 1,242,456 3.35 0.65 rs581318 LOC441075 +56653 bp (XM_499000) 5 60,551,551 3.24 0.25 rs30182 SV2C −30159 bp (XM_043493) 5 75,384,836 3.46 0.84 rs7723981 PTGER4 −275120 bp (NM_000958.2) 5 40,440,669 3.16 0.20 rs10473185 PTGER4 −304865 bp (NM_000958.2) 5 40,410,924 3.06 0.20 rs10041973 ZSWIM6 −51723 bp (XM_035299) 5 60,612,035 3.19 0.11 rs4958734 GALNT10 Intron9 (NM_198321.2), 5 153,769,698 3.05 0.94 GALNT10 Intron2 (NM_017540.3) rs10079115 ZSWIM6 −71664 bp (XM_035299) 5 60,592,094 3.04 0.11 rs4379148 ZSWIM6 −72613 bp (XM_035299) 5 60,591,145 3.03 0.11 rs1501905 SV2C Intron1 (XM_043493) 5 75,433,640 3.04 0.79 rs30196 SV2C −1688 bp (XM_043493) 5 75,413,307 3.06 0.78 rs158563 LOC91942 Intron1 (NM_174889.2) 5 60,290,761 3.44 0.20 rs10939888 ZSWIM6 −72737 bp (XM_035299) 5 60,591,021 3.00 0.14 rs12696980 ZSWIM6 −71733 bp (XM_035299) 5 60,592,025 3.00 0.14 rs2328883 LRRC16 −108438 bp (NM_017640.2) 6 25,510,510 1.85 0.33 rs531970 EPHA7 −35391 bp (NM_004440.2) 6 94,221,384 1.06 0.46 rs880226 LRRC16 −108666 bp (NM_017640.2) 6 25,510,282 2.02 0.33 rs9469615 MLN −45140 bp (NM_002418.1) 6 33,924,911 1.24 0.86 rs600709 NCOA7 Intron2 (NM_1817812) 6 126,175,082 2.48 0.88 rs7767107 LOC441173 Intron1 (XM_496827) 6 142,237,572 3.49 0.30 rs1336272 LOC441173 −23126 bp (XM_96827) 6 142,286,367 3.54 0.31 rs595805 NRN1 −34495 bp (NM_016588.2) 6 5,987,127 1.27 0.65 rs763075 LOC442255 +235684 bp (XM_498140) 6 122,253,219 0.20 0.71 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs2055375 0.15 1.97 3.03 7.10 1.84 rs1560026 0.69 1.26 3.00 0.67 0.33 rs16869864 0.12 2.04 2.96 5.54 2.19 rs7736074 0.52 1.69 2.76 3.00 2.07 rs581318 0.15 1.89 2.75 6.89 1.73 rs30182 0.73 1.89 2.74 4.40 2.54 rs7723981 0.11 2.04 2.67 5.19 2.13 rs10473185 0.11 2.00 2.58 5.23 2.09 rs10041973 0.04 2.75 2.48 ND 2.55 rs4958734 0.87 2.33 2.36 4.20 1.77 rs10079115 0.04 2.68 2.34 ND 2.48 rs4379148 0.04 2.75 2.32 ND 2.53 rs1501905 0.68 1.73 2.29 3.12 1.94 rs30196 0.67 1.72 2.25 2.77 1.65 rs158563 0.10 2.19 2.19 4.28 1.69 rs10939888 0.07 2.26 2.16 6.78 2.02 rs12696980 0.07 2.26 2.16 6.78 2.02 rs2328883 0.25 1.49 3.89 11.95 0.95 rs531970 0.40 1.28 3.84 2.25 0.65 rs880226 0.24 1.53 3.80 11.95 0.99 rs9469615 0.81 1.45 3.52 0.18 0.08 rs600709 0.80 1.80 3.48 0.39 0.16 rs7767107 0.19 1.86 3.35 2.24 2.29 rs1336272 0.19 1.86 3.31 2.37 2.25 rs595805 0.58 1.33 3.31 1.29 0.54 rs763075 0.69 1.08 3.23 0.41 0.22

TABLE 37 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs13213414 LOC441173 Intron1 (XM_496827) 6 142,262,919 3.60 0.31 rs16886390 TMEM30A Intron1 (NM_018247.1) 6 76,038,298 1.18 0.87 rs1322867 TBX18 −222373 bp (XM_496819) 6 85,752,991 1.35 0.35 rs2152589 LOC441173 Intron1 (XM_496827) 6 142,250,761 3.51 0.31 rs3798425 MYO6 Intron29 (XM_376516) 6 76,664,270 2.57 0.83 rs9496008 LOC441173 +181779 bp (XM_496827) 6 141,762,720 3.74 0.54 rs9349248 PHACTR1 −204207 bp (XM_166420) 6 12,621,612 0.77 0.57 rs12200432 PHACTR1 −201248 bp (XM_166420) 6 12,624,571 0.44 0.58 rs6570564 LOC285740 +20195 bp (XM_379438) 6 143,896,965 3.35 0.52 rs9399445 LOC285740 +16163 bp (XM_379438) 6 143,900,997 3.41 0.55 rs4713376 C6orf214 +7329 bp (NM_207496.1) 6 30,881,293 3.37 0.17 rs9484507 LOC441173 +179848 bp (XM_496827) 6 141,764,651 3.93 0.53 rs9379712 C6orf32 −187336 bp (NM_015864.2) 6 25,172,898 3.15 0.59 rs7754052 LOC441173 Intron1 (XM_496827) 6 142,254,496 3.20 0.32 rs9496179 LOC441173 Intron1 (XM_496827) 6 142,254,945 3.20 0.32 rs2039560 LOC441173 +145925 bp (XM_496827) 6 141,798,574 3.40 0.67 rs10485223 PRDM13 −130551 bp (NM_021620.2) 6 100,300,726 3.31 0.79 rs4240580 PRDM13 +138012 bp (NM_021620.2) 6 100,308,187 3.51 0.79 rs9393611 C6orf32 −188810 bp (NM_015864.2) 6 25,174,372 3.03 0.59 rs9356960 C6orf32 −188588 bp (NM_015864.2) 6 25,174,150 3.07 0.59 rs9367520 ELOVL5 Intron1 (NM_021814.2) 6 53,271,883 3.41 0.35 rs12195469 C6orf214 Intron1 (NM_207496.1) 6 30,897,587 3.21 0.16 rs17826560 PRDM13 +132124 bp (NM_021620.2) 6 100,302,299 3.29 0.79 rs1915463 VMP −52946 bp (NM_080723.2) 6 24,181,383 3.24 0.53 rs17070891 LOC441173 +153727 bp (XM_496827) 6 141,790,772 3.27 0.55 rs1402406 VMP −35757 bp (NM_080723.2) 6 24,198,572 3.06 0.57 rs10947096 C6orf214 +14748 bp (NM_207496.1) 6 30,873,874 3.08 0.13 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs13213414 0.19 1.87 3.15 2.59 2.17 rs16886390 0.82 1.47 3.14 0.78 0.27 rs1322867 0.28 1.38 3.14 1.00 2.24 rs2152589 0.20 1.85 3.14 2.52 2.17 rs3798425 0.74 1.70 3.13 1.29 0.56 rs9496008 0.40 1.73 3.04 3.06 1.62 rs9349248 0.52 1.22 3.03 1.32 0.55 rs12200432 0.55 1.14 3.01 1.09 0.49 rs6570564 0.40 1.67 3.00 2.89 2.05 rs9399445 0.42 1.68 2.97 2.98 2.01 rs4713376 0.08 2.27 2.94 3.11 2.51 rs9484507 0.39 1.80 2.93 2.98 1.58 rs9379712 0.47 1.64 2.92 2.80 1.28 rs7754052 0.21 1.77 2.88 2.37 2.09 rs9496179 0.21 1.77 2.88 2.37 2.09 rs2039560 0.54 1.70 2.84 3.04 1.71 rs10485223 0.68 1.80 2.83 4.45 2.68 rs4240580 0.68 1.82 2.81 3.79 2.25 rs9393611 0.47 1.62 2.79 2.70 1.26 rs9356960 0.47 1.63 2.78 2.81 1.33 rs9367520 0.23 1.82 2.76 4.12 1.62 rs12195469 0.08 2.22 2.75 3.06 2.43 rs17826560 0.68 1.79 2.73 4.08 2.50 rs1915463 0.41 1.66 2.61 2.72 1.84 rs17070891 0.42 1.66 2.60 2.79 1.61 rs1402406 0.45 1.62 2.59 2.63 2.00 rs10947096 0.06 2.44 2.57 ND 2.47

TABLE 38 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs9403498 FUCA2 −18431 bp (NM_032020.3) 6 143,892,987 3.04 0.63 rs1402405 VMP −35853 bp (NM_080723.2) 6 24,198,476 3.13 0.58 rs7740547 SLC22A16 Intron1 (NM_033125.2) 6 110,897,601 3.13 0.49 rs221712 SLC22A16 Intron4 (NM_033125.2) 6 110,869,519 3.18 0.49 rs17577123 C6orf10 +2945 bp (NM_006781.2) 6 32,365,525 3.07 0.11 rs7802749 PPP1R9A Intron4 (XM_371933) 7 94,432,292 1.20 0.53 rs6965857 DLD −36997 bp (NM_000108.2) 7 107,088,565 0.76 0.65 rs11972734 CREB3L2 −6085 bp (NM_194071.1) 7 137,150,143 3.19 0.26 rs1621819 C1GALT1 +30350 bp (NM_020156.1) 7 7,087,571 3.80 0.61 rs1514880 LOC340268 Intron1 (XM_294634) 7 9,664,527 3.39 0.60 rs12669138 LOC340268 Intron1 (XM_294634) 7 9,564,997 2.83 0.65 rs698408 SND1 Intron8 (NM_014390.1) 7 126,939,887 2.61 0.30 rs7458284 LOC340268 Intron1 (XM_294634) 7 9,670,774 3.37 0.39 rs3757760 SND1 Intron16 (NM_014390.1) 7 127,252,147 3.23 0.30 rs2241291 SND1 Intron16 (NM_014390.1), 7 127,232,825 3.27 0.30 NAG8 Exon1 (NM_014411.1) rs17156635 CREB5 Intron1 (NM_182899.2), 7 28,168,969 3.16 0.23 CREB5 −56415 bp (NM_182898.1), CREB5 −79505 bp (NM_004904.1) rs1638213 C1GALT1 +33234 bp (NM_020156.1) 7 7,090,455 3.36 0.60 rs320785 LOC340268 −6464 bp (XM_294634) 7 9,532,629 3.41 0.59 rs1796121 C1GALT1 +33624 bp (NM_020156.1) 7 7,090,845 3.24 0.59 rs3757759 SND1 Intron16 (NM_014390.1) 7 127,288,765 3.12 0.33 rs12530870 KIAA1706 −11363 bp (NM_030636.1) 7 35,954,741 3.00 0.81 rs17152703 LOC401384 +195612 bp (XM_379506) 7 78,929,412 3.33 0.85 rs10441198 LOC442363 −76453 bp (XM_498255) 7 144,098,654 3.17 0.60 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs9403498 0.51 1.63 2.56 2.89 2.01 rs1402405 0.45 1.63 2.43 2.63 1.91 rs7740547 0.37 1.64 2.43 2.66 1.33 rs221712 0.37 1.65 2.39 2.64 1.39 rs17577123 0.04 2.71 1.95 3.88 2.47 rs7802749 0.46 1.32 3.58 1.78 0.61 rs6965857 0.60 1.23 3.13 1.00 0.45 rs11972734 0.16 1.86 3.12 15.95 1.54 rs1621819 0.47 1.76 3.11 3.14 2.03 rs1514880 0.46 1.70 3.09 3.25 2.24 rs12669138 0.54 1.60 3.08 3.15 2.74 rs698408 0.21 1.66 3.03 1.55 2.28 rs7458284 0.27 1.74 2.87 3.81 1.44 rs3757760 0.19 1.81 2.85 2.51 2.08 rs2241291 0.19 1.81 2.81 2.63 2.04 rs17156635 0.13 1.99 2.80 14.75 1.50 rs1638213 0.47 1.67 2.72 2.82 1.90 rs320785 0.46 1.68 2.71 2.84 1.73 rs1796121 0.47 1.65 2.58 2.74 1.84 rs3757759 0.22 1.74 2.57 3.27 1.80 rs12530870 0.71 1.76 2.42 3.98 2.76 rs17152703 0.75 1.89 2.37 3.41 2.01 rs10441198 0.48 1.64 2.36 2.41 1.33

TABLE 39 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs13225076 LOC285984 −162101 bp (XM_208373) 7 84,095,361 3.16 0.86 rs17171658 C7orf11 +13816 bp (NM_138701.1) 7 39,931,767 3.02 0.78 rs826824 CNTNAP2 Intron9 (NM_014141.3) 7 146,496,639 3.04 0.74 rs6993934 FBXO16 +12541 bp (NM_172366.2) 8 28,329,307 0.01 0.27 rs1425735 EBF2 +148803 bp (NM_022659.1) 8 25,608,687 1.50 0.66 rs6991277 PTDSS1 +53377 bp (NM_014754.1) 8 97,469,327 3.10 0.93 rs6981589 LOC286186 Intron1 (XM_379586) 8 66,612,011 2.30 0.66 rs4394361 LOC157657 −172125 bp (NM_177965.2) 8 96,522,738 3.55 0.24 rs3133744 LOC157657 −252889 bp (NM_177965.2) 8 96,603,502 3.53 0.31 rs10113800 LOC157657 −163565 bp (NM_177965.2) 8 96,514,178 3.12 0.23 rs6601569 C8orf7 −14730 bp (XM_088376) 8 11,110,988 3.45 0.93 rs10105301 LOC286186 +84181 bp (XM_379586) 8 66,517,616 3.04 0.27 rs6995270 SIAT4A Intron2 (NM_003033.2), 8 134,582,401 3.02 0.51 SIAT4A Intron2 (NM_173344.1) rs10811638 CDKN2A +44473 bp (NM_000077.3), 9 21,913,279 0.15 0.42 CDKN2A +44473 bp (NM_058197.2), CDKN2A +44473 bp (NM_058195.2) rs10869589 PCSK5 −314572 bp (NM_006200.2) 9 75,420,603 2.09 0.72 rs10967964 MOBKL2B Intron1 (NM_024761.3) 9 27,485,920 3.13 0.23 rs2518713 CDKN2A +38086 bp (NM_000077.3), 9 21,919,666 0.38 0.44 CDKN2A +38086 bp (NM_058197.2), CDKN2A +38086 bp (NM_058195.2) rs10781440 LOC392347 Intron1 (XM_373298) 9 68,992,320 3.89 0.37 rs1412066 DBC1 −33786 bp (NM_014618.1) 9 119,245,041 3.06 0.93 rs7022939 LOC347273 +139903 bp (XM_294592) 9 100,568,349 1.91 0.36 rs4744780 PCSK5 Intron9 (NM_006200.2) 9 75,952,602 3.30 0.50 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs13225076 0.76 1.93 2.31 3.53 1.92 rs17171658 0.67 1.75 2.31 2.98 1.70 rs826824 0.63 1.69 2.26 2.60 1.52 rs6993934 0.27 1.00 3.56 0.37 1.81 rs1425735 0.58 1.38 3.28 1.37 0.57 rs6991277 0.85 2.28 3.26 0.74 0.26 rs6981589 0.56 1.52 3.13 2.85 3.04 rs4394361 0.13 2.04 3.09 10.03 1.97 rs3133744 0.19 1.90 2.97 4.79 1.84 rs10113800 0.14 1.92 2.70 10.58 1.76 rs6601569 0.85 2.32 2.66 7.14 3.26 rs10105301 0.17 1.81 2.63 2.22 2.10 rs6995270 0.39 1.62 2.37 2.71 1.49 rs10811638 0.41 1.06 3.80 0.84 2.27 rs10869589 0.63 1.52 3.59 5.09 5.18 rs10967964 0.13 1.95 3.55 1.34 2.62 rs2518713 0.41 1.13 3.39 1.01 2.32 rs10781440 0.24 1.85 3.34 3.48 1.97 rs1412066 0.85 2.19 3.25 0.97 0.35 rs7022939 0.28 1.48 3.21 1.32 2.30 rs4744780 0.37 1.68 3.18 2.85 2.21

TABLE 40 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs4743420 LOC347273 +139198 bp (XM_294592) 9 100,567,644 1.93 0.36 rs10815959 PTPRD −82533 bp (NM_002839.1), 9 8,806,479 3.11 0.58 PTPRD −82533 bp (NM_130391.1), PTPRD −82533 bp (NM_130392.1), PTPRD −82533 bp (NM_130393.1) rs953924 FLJ31810 Intron3 (NM_152570.1) 9 28,313,673 2.54 0.85 rs4836767 DBC1 −34887 bp (NM_014618.1) 9 119,246,142 3.24 0.93 rs4977749 CDKN2A +40425 bp (NM_000077.3), 9 21,917,327 0.38 0.44 CDKN2A +40425 bp (NM_058197.2), CDKN2A +40425 bp (NM_058195.2) rs10512277 LOC347273 +138909 bp (XM_294592) 9 100,567,355 2.02 0.36 rs9299341 LOC347273 +141993 bp (XM_294592) 9 100,570,439 2.02 0.36 rs10491692 DOCK8 Intron13 (NM_203447.1) 9 336,887 0.35 0.16 rs2780197 C9orf39 Intron13 (NM_017738.1) 9 17,416,186 3.83 0.81 rs7038186 C9orf39 Intron10 (NM_017738.1) 9 17,388,616 3.69 0.81 rs2773395 C9orf28 −119663 bp (XM_088525) 9 126,049,019 3.39 0.36 rs1412067 DBCI −35540 bp (NM_014618.1) 9 119,246,795 3.08 0.93 rs11144406 OSTF1 +226491 bp (NM_012383.3) 9 75,217,808 3.39 0.20 rs10869690 PIP5K1B Intron15 (NM_003558.1) 9 68,851,241 3.37 0.38 rs10969339 LOC401497 +655774 bp (XM_376822) 9 29,723,159 3.13 0.88 rs16929359 DMRT2 +392458 bp (NM_006557.3), 9 1,440,010 3.62 0.11 DMRT2 +392458 bp (NM 181872.1) rs943509 OSTF1 +226788 bp (NM_012383.3) 9 75,218,105 3.18 0.37 rs10869686 PIP5K1B Intron15 (NM_003558.1) 9 68,850,168 3.22 0.37 rs10869553 OSTF1 +235138 bp (NM_012383.3) 9 75,226,455 3.09 0.20 rs12554461 RCL1 +4195 bp (NM_005772.2) 9 4,855,256 3.19 0.41 rs4142436 DMRT2 +396648 bp (NM_006557.3), 9 1,444,200 3.23 0.13 DMRT2 +396648 bp (NM_181872.1) High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs4743420 0.27 1.49 3.17 1.33 2.29 rs10815959 0.46 1.63 3.15 2.73 2.41 rs953924 0.77 1.74 3.10 18.06 14.20 rs4836767 0.85 2.24 3.09 1.46 0.53 rs4977749 0.41 1.13 3.09 1.02 2.22 rs10512277 0.27 1.50 3.08 1.41 2.27 rs9299341 0.27 1.50 3.08 1.41 2.27 rs10491692 0.14 1.17 3.08 0.00 1.80 rs2780197 0.70 1.90 3.05 3.93 2.16 rs7038186 0.69 1.87 2.96 3.91 2.20 rs2773395 0.24 1.77 2.94 2.98 1.97 rs1412067 0.85 2.20 2.92 1.45 0.54 rs11144406 0.11 2.10 2.91 5.39 2.22 rs10869690 0.26 1.74 2.85 3.90 1.51 rs10969339 0.79 1.95 2.77 11.71 6.74 rs16929359 0.04 3.02 2.70 ND 2.53 rs943509 0.25 1.72 2.70 3.80 1.45 rs10869686 0.26 1.73 2.68 3.74 1.52 rs10869553 0.11 2.01 2.62 5.19 2.10 rs12554461 0.29 1.69 2.60 2.49 1.90 rs4142436 0.06 2.49 2.54 3.92 2.56

TABLE 41 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs7048937 LOC392347 Intron2 (XM_373298) 9 68,975,807 3.16 0.38 rs7034303 LOC392347 Intron2 (XM_373298) 9 68,976,425 3.16 0.38 rs6560584 LOC392347 Intron2 (XM_373298) 9 68,976,726 3.16 0.38 rs7850573 LOC392347 Intron2 (XM_373298) 9 68,976,814 3.16 0.38 rs2584554 C9orf39 Intron13 (NM_017738.1) 9 17,416,808 3.13 0.80 rs1547335 LOC401497 +621065 bp (XM_376822) 9 29,757,868 3.11 0.77 rs3781158 KCNMA1 Intron18 (NM_002247.2) 10 78,426,444 1.61 0.60 rs10823349 HK1 Intron5 (NM_033497.1), 10 70,779,704 3.56 0.90 HK1 Intron5 (NM_033498.1), HK1 Intron6 (NM_033500.1), HK1 Intron2 (NM_033496.1), HK1 Intron2 (NM_000188.1) rs17388160 KCNMA1 Intron18 (NM_002247.2) 10 78,415,943 1.81 0.66 rs1801041 DNA2L Exon21 (XM_166103) 10 69,844,713 1.49 0.80 rs11001963 KCNMA1 Intron18 (NM_002247.2) 10 78,430,965 2.23 0.70 rs4454609 PHYH +15499 bp (NM_006214.2) 10 13,344,307 2.46 0.66 rs4589168 HK1 Intron10 (NM_033497.1), 10 70,800,223 3.18 0.89 HK1 Intron10 (NM_033498.1), HK1 Intron11 (NM_033500.1), HK1 Intron7 (NM_033496.1), HK1 Intron7 (NM 000188.1) rs7093891 XPNPEP1 +21493 bp (NM_020383.2) 10 111,593,021 3.00 0.69 rs10762840 LOC283050 Intron4 (XM_378238) 10 80,483,339 3.86 0.39 rs9416465 ZWINT +273128 bp (NM_007057.2), 10 57,514,084 3.32 0.82 ZWINT +273128 bp (NM_032997.1) rs7903897 LOC285444 +40505 bp (XM_497256) 10 135,321,566 3.05 0.61 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs7048937 0.27 1.70 2.52 2.57 1.85 rs7034303 0.27 1.70 2.52 2.57 1.85 rs6560584 0.27 1.70 2.52 2.57 1.85 rs7850573 0.27 1.70 2.52 2.57 1.85 rs2584554 0.70 1.78 2.50 3.38 1.91 rs1547335 0.66 1.73 2.25 2.90 1.82 rs3781158 0.51 1.39 3.96 1.65 0.59 rs10823349 0.80 2.13 3.90 1.05 0.39 rs17388160 0.57 1.44 3.79 1.47 0.57 rs1801041 0.73 1.45 3.58 0.78 0.33 rs11001963 0.60 1.52 3.57 1.55 0.63 rs4454609 0.55 1.55 3.56 3.42 3.45 rs4589168 0.81 2.01 3.45 1.15 0.45 rs7093891 0.57 1.64 3.31 2.15 0.92 rs10762840 0.26 1.81 3.12 3.29 1.83 rs9416465 0.71 1.85 2.78 3.55 1.81 rs7903897 0.49 1.63 2.72 2.68 2.21

TABLE 42 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs2496057 C10orf112 Intron20 (XM_295865) 10 19,623,674 3.05 0.56 rs1500763 ZWINT +308458 bp (NM_007057.2), 10 57,478,754 3.03 0.86 ZWINT +308458 bp (NM_032997.1) rs2151078 PCDH15 Intron3 (NM_033056.2) 10 55,864,965 3.11 0.95 rs1881716 LDHA Intron5 (NM_005566.1) 11 18,381,594 3.40 0.38 rs7107489 LOC119710 +809442 bp (NM_138787.2) 11 37,446,835 1.46 0.65 rs6590698 SPAS1 +396277 bp (NM_174927.1) 11 132,819,450 1.09 0.72 rs4274186 LDHA Intron2 (NM_005566.1) 11 18,375,295 3.41 0.38 rs7927545 MGC71806 Intron3 (NM_198516.1) 11 11,403,040 3.75 0.60 rs10792820 PICALM Intron12 (NM_007166.1) 11 85,381,622 0.44 0.49 rs9326253 LOC440070 +34118 bp (XM_498530) 11 119,149,661 0.13 0.60 rs12576681 MGC71806 Intron3 (NM_198516.1) 11 11,402,663 3.67 0.31 rs10837846 LOC387761 −159308 bp (XM_373495) 11 42,393,594 2.69 0.59 rs1462674 LOC387761 −160223 bp (XM_373495) 11 42,394,509 2.71 0.59 rs1386239 LOC338645 Intron5 (XM_370616) 11 24,774,285 2.73 0.11 rs10837854 LOC387761 −227349 bp (XM_373495) 11 42,461,635 2.09 0.56 rs504105 FLJ37874 +3946 bp (NM_182603.1) 11 82,641,607 3.17 0.57 rs524441 FLJ37874 +1045 bp (NM_182603.1) 11 82,638,706 3.11 0.56 rs681367 FLJ37874 +1111 bp (NM_182603.1) 11 82,638,772 3.10 0.56 rs628223 MDS025 +4340 bp (NM_021825.3) 11 82,645,812 3.10 0.56 rs6484897 MGC71806 Intron3 (NM_198516.1) 11 11,401,879 3.15 0.31 rs4937173 KIRREL3 Intron1 (NM 032531.1) 11 126,034,466 3.37 0.43 rs11220587 KIRREL3 Intron1 (NM_032531.1) 11 126,082,725 3.35 0.50 rs2252070 MMP13 −77 bp (NM_002427.2) 11 102,331,749 3.46 0.60 rs693253 KIRREL3 Intron1 (NM_032531.1) 11 126,032,975 3.40 0.44 rs4937174 KIRREL3 Intron1 (NM_032531.1) 11 126,034,593 3.21 0.43 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs2496057 0.44 1.62 2.57 2.75 1.90 rs1500763 0.77 1.88 2.54 5.27 2.80 rs2151078 0.88 2.49 2.21 3.40 1.37 rs1881716 0.26 1.74 3.86 2.09 2.48 rs7107489 0.58 1.37 3.69 2.69 3.66 rs6590698 0.66 1.32 3.60 5.44 6.70 rs4274186 0.26 1.76 3.58 2.15 2.41 rs7927545 0.46 1.73 3.58 3.11 1.30 rs10792820 0.46 1.15 3.46 1.48 0.53 rs9326253 0.59 1.05 3.27 0.73 0.36 rs12576681 0.19 1.88 3.23 6.26 1.53 rs10837846 0.47 1.57 3.09 3.22 2.55 rs1462674 0.47 1.57 3.07 3.22 2.53 rs1386239 0.05 2.48 3.06 0.00 3.10 rs10837854 0.47 1.47 3.05 2.58 2.69 rs504105 0.45 1.64 3.05 2.97 1.30 rs524441 0.44 1.63 2.93 2.90 1.29 rs681367 0.44 1.63 2.91 2.90 1.31 rs628223 0.44 1.63 2.91 2.90 1.31 rs6484897 0.20 1.78 2.90 5.97 1.41 rs4937173 0.31 1.71 2.90 2.75 1.96 rs11220587 0.37 1.68 2.88 2.99 1.31 rs2252070 0.47 1.69 2.82 2.88 1.55 rs693253 0.31 1.71 2.77 2.85 1.82 rs4937174 0.31 1.68 2.74 2.66 1.92

TABLE 43 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs12800710 LPXN Intron7 (NM_004811.1) 11 58,071,116 3.73 0.87 rs10898459 EED Intron6 (NM_003797.2), 11 85,650,587 3.14 0.60 EED Intron6 (NM_152991.1) rs3862632 KIRREL3 Intron1 (NM_032531.1) 11 126,054,713 3.21 0.43 rs11229555 CNTF +15485 bp (NM_000614.2), 11 58,165,263 3.57 0.87 ZFP91-CNTF +15485 bp (NM_170768.1) rs1451316 OR1S2 +1990 bp (XM_166916) 11 57,725,262 3.06 0.53 rs7108068 KIRREL3 Intron1 (NM_032531.1) 11 126,035,753 3.18 0.43 rs10896715 OR1S1 +5325 bp (XM_166917) 11 57,745,095 3.38 0.84 rs2298608 CNTF +11265 bp (NM_000614.2), 11 58,161,043 3.47 0.87 ZFP91-CNTF +11265 bp (NM_170768.1) rs655316 MMP13 −5902 bp (NM_002427.2) 11 102,337,574 3.07 0.58 rs161130 LOC387810 −172677 bp (XM_373513) 11 112,160,184 3.15 0.83 rs7102784 LOC399898 +878 bp (XM_374885) 11 57,813,314 3.08 0.88 rs11175627 LOC400046 +33814 bp (XM_378362) 12 63,691,379 3.08 0.27 rs7302136 DKFZp761O2018 +35186 bp (XM_044062) 12 127,752,520 3.91 0.94 rs11175622 LOC400046 +28983 bp (XM_378362) 12 63,686,548 2.98 0.27 rs7136577 LOC400046 +35244 bp (XM_378362) 12 63,692,809 2.98 0.27 rs2169856 LOC441639 +48092 bp (XM_497345) 12 53,858,919 1.26 0.72 rs7962260 FLJ40126 Intron18 (NM_173599.1), 12 38,510,570 3.77 0.24 SLC2A13 Intron6 (NM_052885.1) rs7296095 LOC440112 −115952 bp (XM_498548) 12 114,337,597 2.55 0.28 rs7959848 LOC401725 +200037 bp (XM_377278) 12 82,248,474 3.88 0.45 rs12227382 DKFZp761O2018 +36420 bp (XM_044062) 12 127,753,754 3.72 0.94 rs11059865 DKFZp761O2018 +34801 bp (XM_044062) 12 127,752,135 3.58 0.94 rs4882448 LOC401725 +200630 bp (XM_377278) 12 82,249,067 3.62 0.44 rs4473002 FLJ40126 Intron18 (NM_73599.1), 12 38,541,898 3.40 0.24 SLC2A13 Intron6 (NM_052885.1) High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs12800710 0.77 2.04 2.73 3.91 2.08 rs10898459 0.48 1.64 2.72 2.89 2.06 rs3862632 0.31 1.68 2.66 2.70 1.86 rs11229555 0.77 2.01 2.59 3.88 2.12 rs1451316 0.41 1.63 2.48 2.53 1.97 rs7108068 0.31 1.67 2.58 2.74 1.79 rs10896715 0.74 1.88 2.51 3.08 1.65 rs2298608 0.77 1.99 2.51 3.83 2.12 rs655316 0.46 1.62 2.49 2.74 1.57 rs161130 0.73 1.83 2.35 3.18 1.78 rs7102784 0.79 1.94 2.25 3.65 1.98 rs11175627 0.17 1.83 3.15 16.90 1.47 rs7302136 0.85 2.54 3.13 5.80 2.27 rs11175622 0.17 1.79 3.10 16.58 1.46 rs7136577 0.17 1.79 3.10 16.58 1.46 rs2169856 0.66 1.35 3.06 0.97 0.45 rs7962260 0.13 2.07 3.05 8.32 1.68 rs7296095 0.19 1.68 3.05 10.32 1.19 rs7959848 0.32 1.79 3.02 3.10 1.75 rs12227382 0.85 2.48 2.94 5.75 2.33 rs11059865 0.86 2.48 2.92 4.34 1.67 rs4882448 0.31 1.76 2.85 3.01 1.76 rs4473002 0.14 1.97 2.82 8.19 1.58

TABLE 44 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs7968509 FLJ40126 Intron18 (NM_173599.1), 12 38,541,115 3.46 0.24 SLC2A13 Intron6 (NM_052885.1) rs7956512 LOC401725 +199585 bp (XM_377278) 12 82,248,022 3.71 0.46 rs4768188 FLJ40126 Intron18 (NM_173599.1), 12 38,507,445 3.46 0.25 SLC2A13 Intron7 (NM_052885.1) rs10877835 SLC2A13 Intron3 (NM_052885.1) 12 38,637,759 3.13 0.15 rs11116586 SLC6A15 +106086 bp (NM_182767.2), 12 83,650,812 3.08 0.73 SLC6A15 +127822 bp (NM_018057.3) rs908440 TRHDE +374236 bp (NM_013381.1) 12 71,719,925 3.11 0.73 rs7485210 LOC116437 −10703 bp (XM_378394) 12 130,163,733 3.19 0.57 rs10862927 SLC6A15 +113194 bp (NM_182767.2), 12 83,643,704 3.01 0.73 SLC6A15 +134930 bp (NM_018057.3) rs4765680 CACNA1C Intron3 (NM_000719.3) 12 2,427,360 3.03 0.96 rs4643164 LOC122335 −355849 bp (XM_063084) 13 106,724,352 0.88 0.38 rs2802402 HTR2A −215185 bp (NM_000621.1) 13 46,583,361 2.21 0.30 rs17640758 DNAJD1 +11297 bp (NM_013238.1) 13 42,590,879 2.16 0.14 rs2282267 CLMN Intron12 (NM_024734.2) 14 94,729,648 3.75 0.69 rs2208986 SLC35F4 −84786 bp (XM_292260) 14 57,218,154 0.82 0.76 rs4304940 SLC35F4 −89221 bp (XM_292260) 14 57,222,589 0.84 0.75 rs1028591 LOC283547 −65737 bp (XM_378454) 14 38,495,490 0.43 0.64 rs7148801 AKAP6 Intron7 (NM_004274.3) 14 32,206,647 3.68 0.95 rs3180753 CLMN Intron12 (NM_024734.2) 14 94,729,500 3.64 0.68 rs2150324 OR4L1 −2371 bp (XM_063310) 14 19,595,673 0.29 0.54 rs10483416 AKAP6 Intron7 (NM_004274.3) 14 32,145,585 3.27 0.81 rs6571593 NPAS3 Intron2 (NM_022123.1), 14 32,865,564 3.22 0.48 NPAS3 Intron3 (NM_173159.1) rs2282273 CLMN Intron11 (NM_024734.2) 14 94,730,437 3.41 0.66 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs7968509 0.13 1.99 2.82 7.74 1.66 rs7956512 0.32 1.75 2.79 2.82 1.72 rs4768188 0.15 2.01 2.69 6.02 1.63 rs10877835 0.07 2.28 2.50 4.03 2.36 rs11116586 0.62 1.68 2.48 2.41 1.27 rs908440 0.62 1.69 2.48 3.10 1.95 rs7485210 0.45 1.64 2.46 2.66 1.59 rs10862927 0.62 1.67 2.40 2.40 1.29 rs4765680 0.90 2.66 2.38 ND ND rs4643164 0.33 1.26 3.63 3.26 0.70 rs2802402 0.21 1.59 3.39 1.16 2.38 rs17640758 0.08 1.91 3.07 0.00 2.48 rs2282267 0.55 1.76 3.33 3.22 1.59 rs2208986 0.71 1.26 3.29 0.70 0.33 rs4304940 0.71 1.27 3.22 0.72 0.34 rs1028591 0.61 1.14 3.20 0.82 0.39 rs7148801 0.88 2.80 3.18 2.11 0.64 rs3180753 0.55 1.74 3.11 3.01 1.53 rs2150324 0.52 1.10 3.07 1.11 0.49 rs10483416 0.70 1.79 2.95 2.07 0.95 rs6571593 0.36 1.67 2.93 2.02 2.29 rs2282273 0.54 1.70 2.91 3.07 1.66

TABLE 45 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs1622029 LOC283583 −1366892 bp (XM_211092) 14 83,697,804 3.52 0.71 rs8003168 RGS6 −36445 bp (NM_004296.3) 14 71,433,141 3.09 0.47 rs10498642 DICER1 Intron9 (NM_030621.2), 14 94,658,292 3.42 0.62 DICER1 Intron8 (NM_177438.1) rs9646147 LRFN5 −190930 bp (NM_152447.2) 14 40,956,160 3.19 0.92 rs1187627 CLMN Intron9 (NM_024734.2) 14 94,734,482 3.50 0.59 SNP_A-18219 MAMDC1 −1035952 bp (NM_182830.2) 14 47,918,097 3.37 0.59 rs14042 FLJ45244 Exon2 (NM_207443.1) 14 94,715,773 3.38 0.56 rs1187626 CLMN Intron9 (NM_024734.2) 14 94,735,610 3.38 0.60 rs1211448 CLMN Intron9 (NM_024734.2) 14 94,734,970 3.28 0.59 rs848117 SLC25A21 Intron3 (NM_030631.1) 14 36,326,610 3.15 0.12 rs12900219 NDN −100017 bp (NM_002487.2) 15 21,583,560 3.84 0.93 rs2247154 TLE3 +105451 bp (NM_005078.1) 15 68,024,022 2.86 0.82 rs12324063 ATP10A Intron3 (NM_024490.2) 15 23,540,049 3.60 0.43 rs16941388 MYO1E −6977 bp (NM_004998.1) 15 57,459,340 3.32 0.94 rs3863401 LRRC28 Intron6 (NM_44598.2) 15 97,698,743 3.59 0.61 rs12591327 TLN2 +69488 bp (NM_015059.1) 15 60,990,221 3.18 0.64 rs7173844 LRRC28 Intron6 (NM_144598.2) 15 97,694,416 3.49 0.61 rs1717831 NDN −95082 bp (NM_002487.2) 15 21,578,625 3.06 0.90 rs4410020 MGC26690 −7119 bp (NM_152450.1) 15 57,510,545 3.02 0.63 rs7198530 CHD9 −179353 bp (NM_025134.2) 16 51,641,067 1.00 0.17 rs9937509 CHD9 −162783 bp (NM_025134.2) 16 51,657,637 1.00 0.18 rs436962 CDH11 +25906 bp (NM_001797.2), 16 63,512,280 1.68 0.84 CDH11 +25906 bp (NM_033664.1) rs4309380 LOC440339 +245434 bp (XM_498634) 16 13,523,196 3.83 0.32 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs1622029 0.58 1.74 2.83 3.23 2.07 rs8003168 0.35 1.64 2.81 2.21 2.13 rs10498642 0.49 1.68 2.80 2.91 1.97 rs9646147 0.84 2.19 2.76 ND ND rs1187627 0.46 1.69 2.75 2.82 1.79 SNP_A-18219 0.47 1.67 2.72 2.68 1.38 rs14042 0.43 1.67 2.72 2.86 1.70 rs1187626 0.47 1.68 2.71 2.88 1.80 rs1211448 0.46 1.66 2.60 2.74 1.82 rs848117 0.05 2.62 2.43 ND 2.34 rs12900219 0.85 2.46 3.79 1.48 0.48 rs2247154 0.72 1.74 3.05 1.62 0.71 rs12324063 0.30 1.74 2.82 2.80 1.82 rs16941388 0.86 2.42 2.79 2.83 1.07 rs3863401 0.48 1.71 2.79 2.85 1.66 rs12591327 0.51 1.65 2.75 2.88 1.51 rs7173844 0.48 1.69 2.70 2.79 1.73 rs1717831 0.82 2.03 2.51 2.45 1.10 rs4410020 0.51 1.64 2.46 2.76 2.01 rs7198530 0.13 1.40 3.77 0.00 2.13 rs9937509 0.14 1.39 3.74 0.00 2.11 rs436962 0.77 1.54 3.73 0.71 0.28 rs4309380 0.20 1.89 3.47 2.73 2.23

TABLE 46 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs35146 CDH11 Intron12 (NM_001797.2), 16 63,541,382 2.24 0.86 CDH11 Intron12 (NM_033664.1) rs35572 LOC390735 −442487 bp (XM_497515) 16 62,385,041 1.02 0.85 rs35165 CDH11 +5537 bp (NM_001797.2), 16 63,532,649 1.89 0.85 CDH11 +5537 bp (NM_033664.1) rs9302502 LOC440339 +251309 bp (XM_498634) 16 13,517,321 3.58 0.33 rs35192 CDH11 Intron4 (NM_001797.2), 16 63,587,141 2.72 0.87 CDH11 Intron4 (NM_033664.1) rs16968101 CDH11 +28144 bp (NM_001797.2), 16 63,510,042 1.89 0.86 CDH11 +28144 bp (NM_033664.1) rs412474 CDH11 +15454 bp (NM_001797.2), 16 63,522,732 2.15 0.86 CDH11 +15454 bp (NM_033664.1) rs429065 CDH11 +22043 bp (NM_001797.2), 16 63,516,143 2.11 0.86 CDH11 +22043 bp (NM_033664.1) rs1554401 CDH11 Intron4 (NM_001797.2), 16 63,588,839 1.62 0.49 CDH11 Intron4 (NM_033664.1) rs35162 CDH11 +5129 bp (NM_001797.2), 16 63,533,057 2.08 0.86 CDH11 +5129 bp (NM_033664.1) rs35216 CDH11 Intron8 (NM_001797.2), 16 63,572,992 2.08 0.86 CDH11 Intron8 (NM_033664.1) rs40116 CDH11 Intron8 (NM_001797.2), 16 63,572,366 2.07 0.86 CDH11 Intron8 (NM_033664.1) rs28216 CDH11 Exon7 (NM_001797.2), 16 63,579,615 2.07 0.86 CDH11 Exon7 (NM_033664.1) High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs35146 0.79 1.70 3.43 0.76 0.31 rs35572 0.81 1.38 3.42 ND ND rs35165 0.78 1.61 3.37 0.67 0.28 rs9302502 0.21 1.84 3.36 2.44 2.24 rs35192 0.78 1.85 3.31 ND ND rs16968101 0.79 1.61 3.30 0.67 0.28 rs412474 0.79 1.68 3.28 0.76 0.32 rs429065 0.79 1.67 3.23 0.76 0.32 rs1554401 0.41 1.39 3.21 2.24 0.76 rs35162 0.79 1.66 3.19 0.75 0.32 rs35216 0.79 1.66 3.15 0.77 0.33 rs40116 0.79 1.65 3.14 0.76 0.33 rs28216 0.79 1.65 3.14 0.76 0.33

TABLE 47 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs35140 CDH11 Intron11 (NM_001797.2), 16 63,548,272 2.03 0.86 CDH11 Intron11 (NM_033664.1) rs9925034 A2BP1 Intron2 (NM_018723.2), 16 6,518,170 1.07 0.48 A2BP1 −804582 bp (NM_145891.1), A2BP1 −804582 bp (NM_145892.1), A2BP1 −804582 bp (NM_145893.1) rs460538 CDH11 +22417 bp (NM_001797.2), 16 63,315,769 2.03 0.86 CDH11 +22417 bp (NM_033664.1) rs1079008 CDH11 Intron2 (NM_001797.2), 16 63,628,424 1.48 0.85 CDH11 Intron2 (NM_033664.1) rs35164 CDH11 +5484 bp (NM_001797.2), 16 63,532,702 1.99 0.86 CDH11 +5484 bp (NM_033664.1) rs35214 CDH11 Intron8 (NM_001797.2), 16 63,573,409 2.02 0.86 CDH11 Intron8 (NM_033664.1) rs35200 CDH11 Intron7 (NM_001797.2), 16 63,579,045 2.02 0.86 CDH11 Intron7 (NM_033664.1) rs13333495 LOC440339 +265091 bp (XM_498634) 16 13,503,539 3.31 0.32 rs16962155 LOC440339 +272794 bp (XM_498634) 16 13,495,836 3.13 0.32 rs6500718 A2BP1 −257472 bp (NM_018723.2), 16 5,751,661 3.43 0.95 A2BP1 −1571091 bp (NM_145891.1), A2BP1 −1571091 bp (NM_145892.1), A2BP1 −1571091 bp (NM_145893.1) rs12595990 LOC92017 Intron9 (XM_042234) 16 12,378,613 3.07 0.51 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs35140 0.79 1.64 3.12 0.75 0.32 rs9925034 0.41 1.29 3.10 1.40 2.42 rs460538 0.79 1.65 3.09 0.76 0.32 rs1079008 0.79 1.49 3.09 0.50 0.23 rs35164 0.79 1.64 3.08 0.74 0.32 rs35214 0.79 1.64 3.08 0.76 0.33 rs35200 0.79 1.64 3.08 0.76 0.33 rs13333495 0.21 1.79 3.03 2.39 2.14 rs16962155 0.21 1.75 2.81 2.34 2.07 rs6500718 0.88 2.65 2.74 ND ND rs12595990 0.39 1.63 2.52 2.69 1.30

TABLE 48 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs8062798 A2BP1 −253070 bp (NM_018723.2), 16 5,756,063 3.02 0.95 A2BP1 −1566689 bp (NM_145891.1), A2BP1 −1566689 bp (NM_45892.1), A2BP1 −1566689 bp (NM_145893.1) rs1816581 CBLN1 +57699 bp (NM_004352.1) 16 47,812,497 3.26 0.41 rs1898359 CBLN1 +57192 bp (NM_004352.1) 16 47,813,004 3.26 0.41 rs9898312 SOCS3 +39255 bp (NM_003955.3) 17 73,825,204 0.49 0.54 rs231005 PMP22 +34074 bp (NM_153322.1), 17 15,039,748 2.71 0.69 PMP22 +34074 bp (NM_153321.1), PMP22 +34074 bp (NM_000304.2) rs10438771 BRIP1 +31746 bp (NM_032043.1) 17 57,083,021 0.02 0.26 rs2074159 LGP2 Intron11 (NM_024119.1) 17 37,510,024 1.71 0.86 rs4890199 RPH3AL +18823 bp (NM_006987.2) 17 43,474 2.70 0.10 rs230923 PMP22 +16078 bp (NM_153322.1), 17 15,057,744 2.05 0.68 PMP22 +16078 bp (NM_153321.1), PMP22 +16078 bp (NM_000304.2) rs1553072 FLJ35773 +12632 bp (NM_152599.2) 17 8,628,576 3.20 0.24 rs917593 MGC45562 Intron2 (NM_152349.1) 17 36,070,052 3.08 0.30 rs17057804 LOC284274 −273821 bp (XM_378756) 18 71,542,467 0.03 0.29 rs11872151 GTSCR1 −653277 bp (XM_496277) 18 67,282,963 2.77 0.97 rs11150900 LOC284274 −284312 bp (XM_378756) 18 71,552,958 0.37 0.67 rs1551434 GTSCR1 −637101 bp (XM_496277) 18 67,266,787 3.59 0.95 rs8098925 LOC400655 −175143 bp (XM_378753) 18 69,257,838 3.34 0.64 rs1828132 LOC284276 Intron2 (XM_378757) 18 72,388,920 3.23 0.52 rs8088082 PPP4R1 −42712 bp (NM_005134.1) 18 9,647,279 3.49 0.21 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs8062798 0.89 2.50 2.38 ND ND rs1816581 0.29 1.70 2.35 2.66 1.60 rs1898359 0.29 1.70 2.35 2.66 1.60 rs9898312 0.50 1.15 3.67 1.43 2.74 rs231005 0.58 1.60 3.43 3.86 3.49 rs10438771 0.25 1.01 3.27 0.44 1.86 rs2074159 0.80 1.57 3.25 ND ND rs4890199 0.04 2.60 3.17 0.48 3.74 rs230923 0.59 1.50 3.06 3.63 3.58 rs1553072 0.14 1.93 2.60 6.76 1.70 rs917593 0.19 1.78 2.35 3.73 1.60 rs17057804 0.29 1.01 3.88 2.55 0.53 rs11872151 0.91 2.74 3.77 0.46 0.10 rs11150900 0.64 1.13 3.50 0.73 0.35 rs1551434 0.87 2.71 3.13 2.07 0.65 rs8098925 0.51 1.69 2.88 2.84 1.41 rs1828132 0.40 1.67 2.81 2.89 1.28 rs8088082 0.11 2.08 2.68 6.23 1.85

TABLE 49 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs2587428 CDH7 +60322 bp (NM_033646.1), 18 61,759,477 3.15 0.50 CDH7 +60323 bp (NM_004361.2) rs6565975 LOC441825 +102358 bp (XM_497596) 18 73,316,910 3.19 0.75 rs10451358 ANKRD12 Intron7 (NM_015208.2) 18 9,207,471 3.05 0.43 rs1942583 LOC441825 +112581 bp (XM_497596) 18 73,327,133 3.02 0.72 rs12051936 LOC441825 +96235 bp (XM_497596) 18 73,310,787 3.11 0.60 rs4482359 LOC440479 +52521 bp (XM_498693) 18 10,180,764 3.16 0.64 rs12462868 FLJ36445 +22374 bp (NM_153233.1) 19 41,163,676 2.44 0.30 rs7260296 NTE +9039 bp (NM_006702.2) 19 7,541,689 0.57 0.62 rs1102152 KCTD15 +36141 bp (NM_024076.1) 19 39,033,129 3.59 0.66 rs4802905 PPP2R1A Intron11 (NM_014225.3) 19 57,415,907 2.59 0.66 rs734380 RPS5 Intron1 (NM_001009.2) 19 63,590,775 2.85 0.52 rs1072678 ZNF600 +14950 bp (NM_198457.1) 19 57,944,329 3.53 0.14 rs734379 RPS5 Intron1 (NM_001009.2) 19 63,590,994 3.11 0.61 rs6132862 LOC400840 +29346 bp (XM_375912) 20 25,669,248 3.95 0.37 rs4572656 PTPRT +22230 bp (NM_007050.3), 20 40,112,577 3.60 0.89 PTPRT +22230 bp (NM_133170.1) rs119416 KCNB1 Intron1 (NM_004975.2) 20 47,469,004 3.98 0.70 rs6019825 KCNB1 Intron1 (NM_004975.2) 20 47,472,824 3.55 0.56 rs6045666 PDYN +18899 bp (NM_024411.2) 20 1,888,504 3.67 0.34 rs6138601 KIAA0980 −32244 bp (NM_025176.3) 20 25,487,486 3.69 0.39 rs6035140 PTPNS1 +15755 bp (NM_080792.1) 20 1,884,292 3.67 0.35 rs12480036 CHD6 Intron1 (NM_032221.3) 20 39,629,243 3.84 0.80 rs6138598 KIAA0980 −6294 bp (NM_025176.3) 20 25,461,536 3.44 0.38 rs517578 SIRPB2 −50868 bp (NM_018556.2), 20 1,637,270 3.30 0.42 SIRPB2 −50868 bp (NM_080816.1) High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs2587428 0.38 1.64 2.60 2.56 1.91 rs6565975 0.63 1.71 2.57 3.30 2.24 rs10451358 0.31 1.65 2.54 3.05 1.32 rs1942583 0.61 1.66 2.42 3.03 2.17 rs12051936 0.47 1.63 2.33 2.56 1.70 rs4482359 0.51 1.66 2.30 2.51 1.46 rs12462868 0.21 1.64 3.69 11.93 1.05 rs7260296 0.58 1.18 3.37 1.89 3.13 rs1102152 0.53 1.73 3.18 2.64 2.56 rs4802905 0.55 1.58 3.13 2.04 0.85 rs734380 0.41 1.59 3.11 2.72 2.35 rs1072678 0.06 2.59 2.92 ND 2.53 rs734379 0.49 1.63 2.86 3.24 1.95 rs6132862 0.24 1.86 3.67 2.58 2.31 rs4572656 0.79 2.08 3.41 1.95 0.77 rs119416 0.56 1.79 3.40 3.04 1.48 rs6019825 0.43 1.70 3.29 3.06 1.30 rs6045666 0.22 1.85 3.28 2.73 2.16 rs6138601 0.26 1.80 3.23 2.64 2.11 rs6035140 0.23 1.83 3.14 2.65 2.09 rs12480036 0.69 1.89 3.13 4.18 2.36 rs6138598 0.26 1.76 3.11 2.45 2.13 rs517578 0.30 1.70 3.11 2.38 2.16

TABLE 50 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs2050223 C20orf23 +550936 bp (NM_024704.3) 20 15,649,814 1.97 0.65 rs926663 MAFB +68744 bp (NM_005461.3) 20 38,679,189 2.89 0.47 rs6072407 CHD6 Intron2 (NM_032221.3) 20 39,596,216 3.83 0.82 rs6138532 ENTPD6 −5585 bp (NM_001247.1) 20 25,118,787 3.00 0.45 rs6083320 CST5 −31324 bp (NM_001900.2) 20 23,839,641 3.26 0.41 rs2076147 ZHX3 Exon4 (NM_015035.2) 20 39,246,420 3.68 0.50 rs1857051 CST5 −33523 bp (NM_001900.2) 20 23,841,840 3.35 0.50 rs4810317 CHD6 +8124 bp (NM_032221.3) 20 39,456,460 3.54 0.81 rs6089908 KCNQ2 Intron10 (NM_004518.2), 20 61,519,098 3.33 0.90 KCNQ2 Intron11 (NM_172106.1), KCNQ2 Intron12 (NM_172107.1), KCNQ2 Intron11 (NM_172108.1), KCNQ2 +16378 bp (NM 172109.1) rs6095508 KCNB1 Intron1 (NM_004975.2) 20 47,461,578 3.30 0.58 rs4812180 LOC284757 +371993 bp (XM_496478) 20 58,704,985 3.73 0.09 rs6115458 FLJ38374 −66026 bp (NM_182583.1) 20 25,917,265 3.19 0.38 rs1321001 CDH22 Intron7 (NM_021248.1) 20 44,250,143 3.08 0.64 rs3761258 C20orf45 −727 bp (NM_016045.1) 20 57,051,991 3.08 0.97 rs94967 LOC150084 +21299 bp (XM_086761) 21 40,117,177 3.96 0.78 rs4816657 LOC150084 Intron4 (XM_086761) 21 40,068,705 3.77 0.77 rs2837211 LOC150084 Intron4 (XM_086761) 21 40,070,264 3.64 0.77 rs1018350 LOC150084 Intron4 (XM_086761) 21 40,070,715 3.64 0.77 rs463903 LOC150084 Intron8 (XM_086761) 21 40,087,547 3.51 0.77 rs2837248 PCP4 −19612 bp (NM_006198.1) 21 40,141,638 3.50 0.67 rs2178882 LOC150084 Intron5 (XM_086761) 21 40,075,682 3.44 0.77 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs2050223 0.56 1.46 3.08 1.66 0.70 rs926663 0.35 1.61 3.08 2.29 2.27 rs6072407 0.71 1.92 3.07 4.47 2.58 rs6138532 0.33 1.66 3.04 2.44 2.24 rs6083320 0.29 1.70 3.02 4.16 1.53 rs2076147 0.37 1.72 3.01 2.99 1.82 rs1857051 0.38 1.68 2.90 3.22 1.65 rs4810317 0.70 1.85 2.89 3.27 1.68 rs6089908 0.81 2.16 2.76 2.60 1.09 rs6095508 0.45 1.67 2.74 2.94 1.83 rs4812180 0.03 3.77 2.72 ND 3.14 rs6115458 0.26 1.71 2.51 2.56 1.84 rs1321001 0.51 1.65 2.47 2.84 1.74 rs3761258 0.92 3.07 2.44 ND ND rs94967 0.65 1.88 3.72 5.80 3.59 rs4816657 0.65 1.83 3.07 3.69 2.12 rs2837211 0.65 1.80 2.96 3.66 2.14 rs1018350 0.65 1.80 2.96 3.66 2.14 rs463903 0.65 1.78 2.86 3.63 2.17 rs2837248 0.55 1.71 2.83 3.10 1.94 rs2178882 0.65 1.80 2.73 3.61 2.20

TABLE 51 High-Risk Allele Critical rate, Frequency in Physical Allele Progressive DBSNP_ID Exon, Intron Chromosome Location (−logP) Glaucoma Group rs4816658 LOC150084 Intron5 (XM_086761) 21 40,075,924 3.53 0.77 rs458406 LOC150084 Intron8 (XM_086761) 21 40,089,698 3.32 0.77 rs2837220 LOC150084 Intron6 (XM_086761) 21 40,082,808 3.39 0.73 rs12627261 LOC150084 Intron6 (XM_086761) 21 40,085,416 3.39 0.73 rs1571713 LOC150084 Intron5 (XM_086761) 21 40,075,065 3.32 0.77 rs2826774 NCAM2 Intron5 (NM_004540.2) 21 21,588,847 3.34 0.60 rs465258 LOC150084 Intron8 (XM_086761) 21 40,093,614 3.22 0.76 rs369977 LOC388814 +131764 bp (XM_373926) 21 15,532,948 3.02 0.68 rs5750009 LOC402059 Intron8 (XM_497817) 22 33,679,879 2.13 0.81 rs1013513 LOC402059 Intron8 (XM_497817) 22 33,678,294 2.12 0.81 rs5999654 LOC402059 Intron8 (XM_497817) 22 33,682,537 2.12 0.81 rs1139056 CECR1 Exon7 (NM_177405.1), 22 16,035,732 3.28 0.26 CECR1 Exon9 (NM_017424.2) rs5759839 LOC388882 Intron4 (XM_371455) 22 22,141,794 3.04 0.59 High-Risk Allele Frequency in Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs4816658 0.65 1.82 2.72 3.32 1.92 rs458406 0.65 1.75 2.69 3.46 2.07 rs2837220 0.61 1.73 2.65 2.91 1.67 rs12627261 0.61 1.73 2.65 2.91 1.67 rs1571713 0.65 1.76 2.65 3.38 1.99 rs2826774 0.47 1.68 2.62 2.81 1.71 rs465258 0.65 1.73 2.62 3.45 2.10 rs369977 0.57 1.64 2.37 2.50 1.39 rs5750009 0.73 1.58 3.68 12.15 11.55 rs1013513 0.73 1.58 3.43 11.57 10.59 rs5999654 0.73 1.58 3.43 11.57 10.59 rs1139056 0.15 1.90 2.50 3.23 1.91 rs5759839 0.47 1.62 2.36 2.61 1.55

Tables 29 to 51 list dbSNP ID number or Affimetrix Array ID number specifying known single nucleotide polymorphisms obtained, the exon, intron information (in a case where a single nucleotide polymorphism exists on a gene, the gene name and the exon or intron in which SNP exists are shown, and in a case where a single nucleotide polymorphism does not exist on a gene, neighboring genes and a distance between the gene and the single nucleotide polymorphism are shown), the chromosome number at which the single nucleotide polymorphism exists, the physical location of the single nucleotide polymorphism, the p-value for an allele according to a chi-square test (−log P), the high-risk allele frequencies in the progressive glaucoma group and the nonprogressive glaucoma group, the odds ratio for an allele, the p-value for a genotype according to a chi-square test (−log P), the odds ratio for a genotype of a homozygote, and the odds ratio for a genotype of a heterozygote. Here, in the tables, a portion of which odds ratio is indicated as ND shows a case where any one of the number of detection in the denominator is 0, so that the odds ratio could not be calculated.

According to the above studies, 480 single nucleotide polymorphisms of which alleles or genotypes were associated with the progression of glaucoma at a p-value of 1×10⁻³ or less were found.

When the allele or genotype frequencies listed in Tables 29 to 51 were compared between the progressive glaucoma cases and the nonprogressive glaucoma cases, a statistical difference was found. By determining an allele of any one of these single nucleotide polymorphisms, whether or not an allele that is identified in a higher frequency in the progressive glaucoma group than that of the nonprogressive glaucoma group exists in the sample can be determined.

Example 5 Confirmation of Novel Single Nucleotide Polymorphisms by Sequencing Method of Surrounding of Specified Single Nucleotide Polymorphisms

Surrounding sequences of single nucleotide polymorphisms described in Tables 1 to 2 or Tables 26 to 28 are subjected to re-sequencing, so that the detection of a single nucleotide polymorphism can be confirmed, and that an unknown single nucleotide polymorphism that possibly exists can be identified. The re-sequencing can be performed according to any known methods, and for example, the re-sequencing can be performed by a direct sequencing method.

Example 6

In order to determine the single nucleotide polymorphisms associated with glaucoma identified in Example 3 or 4, or the alleles and genotypes of known single nucleotide polymorphisms existing in the surrounding sequences of the single nucleotide polymorphisms listed in Tables 1 to 51, an immobilized probe can be prepared. A known single nucleotide polymorphism can be referred to, for example, the database of dbSNP or J SNP. In the immobilized probe, for example, an oligonucleotide probe designed so as to maximize its sensitivity, specificity or reproducibility for several probes to several hundred-thousand probes can be loaded. The immobilized probe can be produced according to a method such as a method of synthesizing an oligonucleotide on a solid carrier or a method including the steps of previously synthesizing an oligonucleotide and immobilizing the oligonucleotide in a high density on a solid carrier.

Example 7

The presence or the absence of the onset of glaucoma can be determined at a more accurate level using the immobilized probe produced in Example 6. A probe for detecting a single nucleotide polymorphism associated with a disease is plurally combined, so that the level of which the onset risk of glaucoma increases is evaluated. In a case where a value exceeds a threshold, it is determined that the onset of glaucoma takes place.

In addition, using the immobilized probe produced in Example 6, the single nucleotide polymorphism existing on the genome of the glaucoma patients and that of the non-glaucoma patients can be compared. There is a possibility that single nucleotide polymorphisms existing in locations with an adjacent distance to each other are linked and inherited by linkage disequilibrium. There is a possibility that single nucleotide polymorphisms linked with the single nucleotide polymorphisms listed in Tables 1 and 2 or Tables 26 to 28 can be identified by the immobilized probe, so that it can be expected that a single nucleotide polymorphism having an even stronger association with glaucoma is found.

Example 8 Design of Custom Array

In order to maintain a statistical power while lowering type I error, candidate single nucleotide polymorphisms associated with the onset of glaucoma identified in the primary analysis of Example 3 were subjected to a secondary analysis of a single nucleotide polymorphism in separately collected samples using an array for analyzing a single nucleotide polymorphism designed in an original style (hereinafter, referred to as a custom array).

For the custom array, a kit for analyzing a single nucleotide polymorphism commercially available from Illumina [Illumina, iSelect™ Genotyping BeadChip] was used. For 446 single nucleotide polymorphisms associated with the onset of glaucoma showing a p-value of 1×10⁻³ or less in Example 3, the designing of a probe for specifically detecting these single nucleotide polymorphisms was tried. Since these probes are randomly immobilized to the substrate via beads, the step of specifying a location of the beads (decoding) is needed. A probe for detecting a single nucleotide polymorphism of which location was unable to be specified in a process of decoding was excluded from the subject for analysis. As a result, the preparation of a custom array capable of typing 412 single nucleotide polymorphisms out of 446 single nucleotide polymorphisms is made possible, and the custom array was used in the analysis of a single nucleotide polymorphism described later. Here, as described in the section of Infinium (registered trademark) assay in a beads-array method, in these assay methods, there are two methods, i.e. a method using one kind of a probe and a method using two kinds of probes. Basically, in the detection of one single nucleotide polymorphism, one kind of the probe was used, and two probes were used for some single nucleotide polymorphisms.

Example 9 Analysis of Single Nucleotide Polymorphism Using Custom Array

The experiment was performed in accordance with the instruction manuals of the custom array kit and the analyzing instrument of Illumina, using specialized reagents contained in the kit. Briefly, the experimental procedures will be explained as follows. A reagent specialized in the treatment of the genome and a sodium hydroxide solution were added to 150 to 300 ng of the total DNA extracted in Example 1. Next, an enzyme for amplifying a whole genome was added thereto, and the mixture was incubated at 37° C. for 20 to 24 hours, and a whole genome was amplified. Further, an enzyme for fragmentation was added thereto, and the mixture was incubated at 37° C. for one hour. After the DNA was precipitated with isopropanol, a reagent for solubilization was added to the precipitates, and the mixture was suspended at 48° C. for one hour. A mixture was heat-denatured at 95° C. for 20 minutes, and this solution was injected into the custom array, and hybridization was carried out at 48° C. for 16 to 24 hours.

After the hybridization, an allele-specific extension reaction or a single base extension reaction was performed for each probe, and the fluorescent signals were amplified. The signals were read with a scanner (Illumina, BeadArray Reader) compatible to the kit. In addition, a specialized software (Illumina, BeadStudio 3.1) was used in the analysis of the single nucleotide polymorphisms. According to the present analytical method, the opposite alleles of a single nucleotide polymorphism can be determined simultaneously, and the genotypes were determined on the basis of the analytical results. The genotype was determined to be a heterozygote when both the signals of each of the alleles constituting a single nucleotide polymorphism were detected, and the genotype was determined to be a homozygote of the detected allele when only one of the signals of the alleles was detected.

The precision of the determination of a genotype was confirmed for all the single nucleotide polymorphisms to be analyzed on the basis of a cluster image showing a distribution of fluorescent signals, in accordance with Infinium (registered trademark) Genotyping Data Analysis, an analyzing manual of Illumina. The genotypes of the single nucleotide polymorphisms that are determined accurately are indicated on the image as three clusters of fluorescent signals that are completely separated from each other (two kinds of homozygotes and a heterozygote).

On the other hand, boundary lines of the three clusters become unclear for the single nucleotide polymorphisms that are not determined accurately. In a case where a degree of separation of the clusters is determined not to be high according to analysis software, the cluster image of the single nucleotide polymorphism was reconfirmed. In a case where a genotype was determined regardless of unclearness of the clusters, the sample was excluded from the subsequent analytical operations. Here, the confirmation of the cluster image was carried out under masking, in other words, in a state that the names of single nucleotide polymorphisms and p-values could not be compared with the single nucleotide polymorphisms. Here, the single nucleotide polymorphisms overlapping between the custom array used in the secondary analysis and GeneChip Human Mapping 500K of Affimetrix used in the primary analysis showed a concordance rate of 99% or more, when the concordance rates of the determination of genotypes were compared using 104 samples.

Example 10 Determination of Genotypes in Glaucoma Patients and Non-Patients

Primary open-angle glaucoma patients and normal tension glaucoma patients diagnosed on the basis of Guidelines offered by Japan Glaucoma Society were assigned to a glaucoma patient group, and healthy individuals confirmed to have no family history of glaucoma according to a medical interview were assigned to a non-patient group. For the present analysis, the same samples used in Example 3 for performing the primary analysis were not used, and new samples were collected. Blood donated under the consent on free will of the participants after having sufficiently explained the contents of studies from 409 cases of the glaucoma patient group and 448 controls of the non-patient group, each group being different from those of Example 3 was used as a specimen, a total DNA was extracted according to the method described in Example 1, and the analysis of single nucleotide polymorphisms was performed according to the method described in Example 9. The analytical results of a single nucleotide polymorphism obtained in each of the patients were stored in the Laboratory Information Management System (World Fusion, LaboServer) adopting a relational database. A specialized analysis program for a single nucleotide polymorphism was created and loaded within the system, and the analysis described as follows was performed. In detail, a single nucleotide polymorphism considered to have a high experimental reliability was extracted by rejecting a single nucleotide polymorphism having a call rate of less than 90% in both the glaucoma patient group and the non-patient group, and a single nucleotide polymorphism having a minor allele frequency of less than 5%.

Example 11 Meta-Analysis

In a meta-analysis, the Mantel-Haenszel method was used (Wakariyasui Igaku Tokeigaku (Easy Medical Statistics), pp. 48-80, Toshio MORIZANE, Medical Tribune). In detail, 402 single nucleotide polymorphisms considered to have a high experimental reliability in both of the methods described in Example 3 and Example 10 were subjected to statistical comparisons of the allele frequency and two genotype frequencies (a dominant genetic model and a recessive genetic model) using Mantel-Haenszel chi-square test. Single nucleotide polymorphisms of which any one of an allele model, a dominant genetic model, and a recessive genetic model shows association with the onset of glaucoma at a p-value of 1.2×10⁻⁴ or less (the level of Bonferroni correction corresponding to p<5×10⁻² when 402 times of multiple comparisons were performed), that is, −log P of 3.91 or more, are listed in Table 52.

The calculations of the Mantel-Haenszel chi-square test, and the odds ratio in the Mantel-Haenszel method for these single nucleotide polymorphisms, and a 95% confidence interval were performed according to the following procedures.

A Mantel-Haenszel chi-square value was determined for the allele model, the dominant genetic model, and the recessive genetic model, and a p-value was calculated by comparing the value with the chi-square distribution of a degree of freedom of 1.

The Mantel-Haenszel chi-square value (χA_(MH) ²) of the allele model was calculated according to the following formulas.

EA _(i) =xA _(i) mA _(i) /NA _(i)

${VA}_{i} = \frac{{mA}_{i}{nA}_{i}{xA}_{i}{yA}_{i}}{{NA}_{i}^{2}\left( {{NA}_{i} - 1} \right)}$ ${\chi \; A_{MH}^{2}} = \frac{\left\lbrack {{{\sum\limits_{i = 1}^{k}\left( {{hA}_{i} - {EA}_{i}} \right)}} - 0.5} \right\rbrack^{2}}{\sum\limits_{i = 1}^{k}{VA}_{i}}$

-   xA_(i): a total number of detection of a high-risk allele, -   yA_(i): a total number of detection of a low-risk allele, -   mA_(i): a total number of detection of alleles in the glaucoma     patient group, -   nA_(i): a total number of detection of alleles in the non-patient     group, -   NA_(i): a total number of detection of alleles, and -   hA_(i): the number of detection of a high-risk allele in the     glaucoma patient group.

The Mantel-Haenszel chi-square value (χD_(MH) ²) of the dominant genetic model was calculated according to the following formulas.

ED _(i) =xD _(i) mD _(i) /ND _(i)

${VD}_{i} = \frac{{mD}_{i}{nD}_{i}{xD}_{i}{yD}_{i}}{{ND}_{i}^{2}\left( {{ND}_{i} - 1} \right)}$ ${\chi \; D_{MH}^{2}} = \frac{\left\lbrack {{{\sum\limits_{i = 1}^{k}\left( {{hD}_{i} - {ED}_{i}} \right)}} - 0.5} \right\rbrack^{2}}{\sum\limits_{i = 1}^{k}{VD}_{i}}$

-   xD_(i): the sum of a total number of detection of a homozygote of a     high-risk allele and a total number of detection of a heterozygote, -   yD_(i): a total number of detection of a homozygote of a low-risk     allele, -   mD_(i): a total number of detection of genotypes in the glaucoma     patient group, -   nD_(i): a total number of detection of genotypes in the non-patient     group, -   ND_(i): a total number of detection of genotypes, and -   hD_(i): the sum of the number of detection of a homozygote of a     high-risk allele and the number of detection of a heterozygote in     the glaucoma patient group.

The Mantel-Haenszel chi-square value (χR_(MH) ²) of the recessive genetic model was calculated according to the following formulas.

ER _(i) =xR _(i) mR _(i) /NR _(i)

${VR}_{i} = \frac{{mR}_{i}{nR}_{i}{xR}_{i}{yR}_{i}}{{NR}_{i}^{2}\left( {{NR}_{i} - 1} \right)}$ ${\chi \; R_{MH}^{2}} = \frac{\left\lbrack {{{\sum\limits_{i = 1}^{k}\left( {{hR}_{i} - {ER}_{i}} \right)}} - 0.5} \right\rbrack^{2}}{\sum\limits_{i = 1}^{k}{VR}_{i}}$

-   xR_(i): a total number of detection of a homozygote of a high-risk     allele, -   yR_(i): the sum of a total number of detection of a homozygote of a     low-risk allele and a total number of detection of a heterozygote of     a genotype, -   mR_(i): a total number of detection of genotypes in the glaucoma     patient group, -   nR_(i): a total number of detection of genotypes in the non-patient     group, -   NR_(i): a total number of detection of genotypes, and -   hR_(i): the number of detection of a homozygote of a high-risk     allele in the glaucoma patient group.

The odds ratio in the Mantel-Haenszel test was calculated for the allele model, the dominant genetic model, and the recessive genetic model.

The odds ratio in the Mantel-Haenszel test (ORa_(MH)) for the allele model was calculated according to the following formula.

${ORa}_{MH} = \frac{\sum\limits_{i = 1}^{k}{{Aa}_{i}{{Da}_{i}/{Za}_{i}}}}{\sum\limits_{i = 1}^{k}{{Ba}_{i}{{Ca}_{i}/{Za}_{i}}}}$

-   Aa_(i): the number of detection of a high-risk allele in the     glaucoma patient group, -   Ba_(i): the number of detection of a low-risk allele in the glaucoma     patient group, -   Ca_(i): the number of detection of a high-risk allele in the     non-patient group, -   Da_(i): the number of detection of a low-risk allele in the     non-patient group, and -   Za_(i): a total number of detection of alleles.

The odds ratio in the Mantel-Haenszel test (ORd_(MH)) for the dominant genetic model was calculated according to the following formula.

${ORd}_{MH} = \frac{\sum\limits_{i = 1}^{k}{{Ad}_{i}{{Dd}_{i}/{Zd}_{i}}}}{\sum\limits_{i = 1}^{k}{{Bd}_{i}{{Cd}_{i}/{Zd}_{i}}}}$

-   Ad_(i): the sum of the number of detection of a homozygote of a     high-risk allele in the glaucoma patient group and the number of     detection of a heterozygote in the glaucoma patient group, -   Bd_(i): the number of detection of a homozygote of a low-risk allele     in the glaucoma patient group, -   Cd_(i): the sum of the number of detection of a homozygote of a     high-risk allele in the non-patient group and the number of     detection of a heterozygote in the non-patient group, -   Dd_(i): the number of detection of a homozygote of a low-risk allele     in the non-patient group, and -   Zd_(i): a total number of detection of genotypes.

The odds ratio in the Mantel-Haenszel test (ORr_(MH)) for the recessive genetic model was calculated according to the following formula.

${ORr}_{MH} = \frac{\sum\limits_{i = 1}^{k}{{Ar}_{i}{{Dr}_{i}/{Zr}_{i}}}}{\sum\limits_{i = 1}^{k}{{Br}_{i}{{Cr}_{i}/{Zr}_{i}}}}$

-   Ar_(i): the number of detection of a homozygote of a high-risk     allele in the glaucoma patient group, -   Br_(i): the sum of the number of detection of a heterozygote in the     glaucoma patient group and the number of detection of a homozygote     of a low-risk allele in the glaucoma patient group, -   Cr_(i): the number of detection of a homozygote of a high-risk     allele in the non-patient group, -   Dr_(i): the sum of the number of detection of a heterozygote in the     non-patient group and the number of detection of a homozygote of a     low-risk allele in the non-patient group, and -   Zr_(i): a total number of detection of genotypes.

A 95% confidence interval of the odds ratio in the Mantel-Haenszel test was calculated for the allele model, the dominant genetic model, and the recessive genetic model.

The 95% confidence interval (95% CI_(A)) for the allele model was calculated according to the following formulas.

${{PA}_{i} = \frac{{aA}_{i} + {dA}_{i}}{{zA}_{i}}},{{QAi} = \frac{{bA}_{i} + {cA}_{i}}{{zA}_{i}}},{{RA}_{i} = \frac{{aA}_{i}{dA}_{i}}{{zA}_{i}}},{{SA}_{i} = \frac{{bA}_{i}{cA}_{i}}{{zA}_{i}}}$ ${VarA} = {\frac{\sum\limits_{i = 1}^{k}{{PA}_{i}{RA}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{RA}_{i}} \right)} + \frac{\sum\limits_{i = 1}^{k}\left( {{{PA}_{i}{SA}_{i}} + {{QA}_{i}{RA}_{i}}} \right)}{2{\sum\limits_{i = 1}^{k}{{RA}_{i}{\sum\limits_{i = 1}^{k}{SA}_{i}}}}} + \frac{\sum\limits_{i = 1}^{k}{{QA}_{i}{SA}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{SA}_{i}} \right)^{2}}}$ 95% CI _(A)=exp(log ORa _(MH)±1.96√{square root over (VarA)})

-   aA_(i): the number of detection of a high-risk allele in the     glaucoma patient group, -   bA_(i): the number of detection of a low-risk allele in the glaucoma     patient group, -   cA_(i): the number of detection of a high-risk allele in the     non-patient group, -   dA_(i): the number of detection of a low-risk allele in the     non-patient group, -   zA_(i): a total number of detection of alleles, and -   ORa_(MH): an odds ratio in Mantel-Haenszel test for an allele model.

A 95% confidence interval (95% CI_(d)) for the dominant genetic model was calculated according to the following formulas.

${{PD}_{i} = \frac{{aD}_{i} + {dD}_{i}}{{zD}_{i}}},{{QDi} = \frac{{bD}_{i} + {cD}_{i}}{{zD}_{i}}},{{RD}_{i} = \frac{{aD}_{i}{dD}_{i}}{{zD}_{i}}},{{SD}_{i} = \frac{{bD}_{i}{cD}_{i}}{{zD}_{i}}}$ ${VarD} = {\frac{\sum\limits_{i = 1}^{k}{{PD}_{i}{RD}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{RD}_{i}} \right)} + \frac{\sum\limits_{i = 1}^{k}\left( {{{PD}_{i}{SD}_{i}} + {{QD}_{i}{RD}_{i}}} \right)}{2{\sum\limits_{i = 1}^{k}{{RD}_{i}{\sum\limits_{i = 1}^{k}{SD}_{i}}}}} + \frac{\sum\limits_{i = 1}^{k}{{QD}_{i}{SD}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{SD}_{i}} \right)^{2}}}$ 95% CI _(d)=exp(log ORd±1.96√{square root over (VarD)})

-   aD_(i): the sum of the number of detection of a homozygote of a     high-risk allele in the glaucoma patient group and the number of     detection of a heterozygote in the glaucoma patient group, -   bD_(i): the number of detection of a homozygote of a low-risk allele     in the glaucoma patient group, -   cD_(i): the sum of the number of detection of a homozygote of a     high-risk allele in the non-patient group and the number of     detection of a heterozygote in the non-patient group, -   dD_(i): the number of detection of a homozygote of a low-risk allele     in the non-patient group, -   zD_(i): a total number of detection of genotypes, and -   ORd_(MH): an odds ratio in Mantel-Haenszel test for a dominant     genetic model.

A 95% confidence interval (95% CI_(r)) for the recessive genetic model was calculated according to the following formulas.

${{PR}_{i} = \frac{{aR}_{i} + {dR}_{i}}{{zR}_{i}}},{{QRi} = \frac{{bR}_{i} + {cR}_{i}}{{zR}_{i}}},{{RR}_{i} = \frac{{aR}_{i}{dR}_{i}}{{zR}_{i}}},{{SR}_{i} = \frac{{bR}_{i}{cR}_{i}}{{zR}_{i}}}$ ${VarR} = {\frac{\sum\limits_{i = 1}^{k}{{PR}_{i}{RR}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{RR}_{i}} \right)} + \frac{\sum\limits_{i = 1}^{k}\left( {{{PR}_{i}{SR}_{i}} + {{QR}_{i}{RR}_{i}}} \right)}{2{\sum\limits_{i = 1}^{k}{{RR}_{i}{\sum\limits_{i = 1}^{k}{SR}_{i}}}}} + \frac{\sum\limits_{i = 1}^{k}{{QR}_{i}{SR}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{SR}_{i}} \right)^{2}}}$ 95% CI _(r)=exp(log ORr _(MH)±1.96√{square root over (VarR)})

-   aR_(i): the number of detection of a homozygote of a high-risk     allele in the glaucoma patient group, -   bR_(i): the sum of the number of detection of a heterozygote in the     glaucoma patient group and the number of detection of a homozygote     of a low-risk allele in the glaucoma patient group, -   cR_(i): the number of detection of a homozygote of a high-risk     allele in the non-patient group, -   dR_(i): the sum of the number of detection of a heterozygote in the     non-patient group and the number of detection of a homozygote of a     low-risk allele in the non-patient group, -   zR_(i): a total number of detection of genotypes, and -   ORr_(MH): an odds ratio in Mantel-Haenszel test for a recessive     genetic model.

TABLE 52 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Link- Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron age

1 2 Allele Patient Group Group rs4516662 4 140,178,445 CCRN4L −116103 bp (NM_012118.2) LD1 C G C 0.56 0.51 rs13110551 4 140,178,323 CCRN4L −116225 bp (NM_012118.2) LD1 A G G 0.58 0.52 rs11123034 2 124,776,617 CNTNAP5 Intron3 (NM_130773.2), LD2 A G G 0.59 0.54 CNTNAP5 Intron3 (NM_138996.1) rs12611812 1 124,776,344 CNTNAP5 Intron3 (NM_130773.2), LD2 A T A 0.59 0.54 CNTNAP5 Intron3 (NM_138996.1) rs7961953 12 81,594,304 DKFZp762A217 Intron1 (NM_152588.1) A G A 0.33 0.26 rs6451268 5 36,291,121 FLJ25422 Intron11 (NM_145000.2) A G G 0.62 0.58 rs7559118 2 133,706,762 FLJ34870 Intron4 (NM_207481.1) A G G 0.64 0.58 rs7850541 9 133,

,108 GBGT1 −11253 bp (NM_021996.3) A G G 0.78 0.72 rs9358578 6 22,810,626 LOC389370 Intron1 (XM_374162) A G A 0.45 0.38 rs16935718 8 70,265,523 LOC389667 +60391 bp (XM_372046) LD3 A G A 0.74 0.68 rs16935744 8 70,

,548 LOC389867 +75414 bp (XM_372046) LD3 A C C 0.74 0.68 rs705994 8 70,293,144 LOC389667 +90010 bp (XM_372046) LD3 A G G 0.71 0.65 rs10517356 4 62,947,647 LOC391656 −135832 bp (XM_373027) A G G 0.51 0.46 rs7081435 10 20,678,891 PLXDC2 +69770 bp (NM_002812.7) A C A 0.83 0.76 rs547984 1 234,422,927 ZP4 −42931 bp (NM_021186.2) LD4 A C A 0.54 0.46 rs540782 1 234,423,080 ZP4 −43104 bp (NM_021186.2) LD4 C G G 0.54 0.46 rs693471 1 234,425,131 ZP4 −45155 bp (NM_021186.2) LD4 A C A 0.53 0.46 rs2499601 1 234,430,934 ZP4 −50968 bp (NM_021186.2) LD4 A G G 0.53 0.46 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs4516662 0.000021 Dominant 1.7 1.4-2.3 SEQ ID No: 203 SEQ ID No: 204 SEQ ID No: 515 SEQ ID No: 533 rs13110551 0.000004 Dominant 1.9 1.4-2.6 SEQ ID No: 205 SEQ ID No: 206 SEQ ID No: 516 rs11123034 0.000074 Recessive 1.6 1.2-1.9 SEQ ID No: 207 SEQ ID No: 208 SEQ ID No: 517 rs12611812 0.000074 Recessive 1.6 1.2-1.9 SEQ ID No: 209 SEQ ID No: 210 SEQ ID No: 518 SEQ ID No: 534 rs7961953 0.000067 Allele 1.4 1.2-1.6 SEQ ID No: 211 SEQ ID No: 212 SEQ ID No: 519 rs6451268 0.000072 Dominant 1.8 1.3-2.3 SEQ ID No: 213 SEQ ID No: 214 SEQ ID No: 520 rs7559118 0.000005 Dominant 1.9 1.4-2.5 SEQ ID No: 215 SEQ ID No: 216 SEQ ID No: 521 rs7850541 0.000109 Allele 1.4 1.2-1.6 SEQ ID No: 217 SEQ ID No: 218 SEQ ID No: 522 rs9358578 0.000106 Allele 1.3 1.2-1.5 SEQ ID No: 219 SEQ ID No: 220 SEQ ID No: 523 rs16935718 0.000017 Dominant 2.4 1.6-3.5 SEQ ID No: 221 SEQ ID No: 222 SEQ ID No: 524 rs16935744 0.000024 Dominant 2.3 1.6-3.4 SEQ ID No: 223 SEQ ID No: 224 SEQ ID No: 525 rs705994 0.000030 Dominant 2.1 1.5-2.9 SEQ ID No: 225 SEQ ID No: 226 SEQ ID No: 526 rs10517356 0.000067 Dominant 1.6 1.3-2  SEQ ID No: 227 SEQ ID No: 228 SEQ ID No: 527 rs7081435 0.000010 Allele 1.5 1.2-1.8 SEQ ID No: 229 SEQ ID No: 230 SEQ ID No: 528 rs547984 0.000056 Allele 1.3 1.2-1.5 SEQ ID No: 231 SEQ ID No: 232 SEQ ID No: 529 rs540782 0.000054 Dominant 1.6 1.3-2  SEQ ID No: 233 SEQ ID No: 234 SEQ ID No: 530 SEQ ID No: 535 rs693471 0.000032 Dominant 1.6 1.3-2  SEQ ID No: 235 SEQ ID No: 236 SEQ ID No: 531 rs2499601 0.000078 Dominant 1.6 1.3-2  SEQ ID No: 237 SEQ ID No: 238 SEQ ID No: 532

indicates data missing or illegible when filed

Table 52 lists dbSNP ID number specifying known single nucleotide polymorphisms obtained, the chromosome number at which a single nucleotide polymorphism exists, the physical location of a single nucleotide polymorphism, the exon, intron information (in a case where a single nucleotide polymorphism exists on a gene, the gene name and the exon or intron in which SNP exists are shown, and in a case where a single nucleotide polymorphism does not exist on a gene, neighboring genes and a distance between the gene and the single nucleotide polymorphism are shown), the information on the linkage disequilibrium state (the numbers of LD1 to LD4 were assigned to single nucleotide polymorphisms which exist in the same linkage disequilibrium region), each of bases constituting Allele 1 and Allele 2, the base of a high-risk allele, high-risk allele frequencies of the glaucoma patient group and the non-patient group, the p-value in a test method having the lowest p-value among three Mantel-Haenszel tests (allele frequency, dominant genetic model, and recessive genetic model), the kinds of the tests thereof, the odds ratio thereof, the 95% confidence interval thereof, SEQ ID NO: of the sequence containing Allele 1 and SEQ ID NO: of the sequence containing Allele 2 in each of the polymorphic sites, and SEQ ID NO: showing a base sequence of a probe used in a secondary analysis (basically, both the alleles are detected by the same probe, and in a case where the alleles are discriminated using two kinds of probes, both the sequences are listed together). Here, one of ordinary skill in the art can obtain the information for sequences or alleles of the single nucleotide polymorphisms from dbSNP ID number listed above.

When the allele or genotype frequencies of the single nucleotide polymorphisms listed in Table 52 were compared between the non-patients and the glaucoma patients, a statistical difference was found according to Mantel-Haenszel chi-square test. By determining an allele of any one of these single nucleotide polymorphisms in the same manner as that in Example 3, whether or not an allele that is identified in a higher frequency in the glaucoma patient group than that of the non-patient group exists in the sample can be determined.

According to the above studies, 18 single nucleotide polymorphisms of which alleles or genotypes were associated with glaucoma at a p-value of 1.2×10⁻⁴ or less existing in clusters in relatively adjacent regions on the genome were found in 11 regions.

An allele identified in a high frequency in the glaucoma patient group for single nucleotide polymorphisms listed in Table 52 (in other words, a high-risk allele) or a genotype (in other words, a homozygote of a high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or a homozygote of a high-risk allele when the high-risk allele complies with a recessive genetic model) can be used as a marker showing that an onset risk of glaucoma is high. On the other hand, an allele that is opposite to the allele or a genotype other than the genotype can be used as a marker showing that an onset risk of glaucoma is low.

Similarly, a single nucleotide polymorphism of which allele or genotype shows association with the onset of glaucoma at a p-value of 1×10⁻² or less, i.e. −log P of 2 or more is listed in Tables 53 to 62.

TABLE 53 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs429419 5 33,624,092 ADAMTS12 Intron17 (NM_030955.1) C G G 0.91 0.87 rs818725 5 33,624,060 ADAMTS12 Intron17 (NM_030955.1) C G G 0.91 0.87 rs10902569 15 98,663,829 ADAMTS17 Intron3 (NM_139057.1) A G A 0.33 0.33 rs2387658 10 1,413,905 ADARB2 Intron1 (NM_018702.1) A C C 0.75 0.75 rs9881866 3 106,304,709 ALCAM −264171 bp (NM_001627.1) A G G 0.14 0.11 rs1342022 9 72,935,061 ANXA1 −61274 bp (NM_000700.1) A G G 0.59 0.54 rs6097745 20 52,101,533 BCA51 Intron3 (NM_003657.1) A G A 0.30 0.27 rs2816632 14 104,812,400 BRF1 Intron2 (NM_001519.2), A G G 0.21 0.16 BRF1 −27133 bp (NM_145685.1), BRF1 −26567 bp (NM_145696.1) rs16940484 18 19,936,298 C18orf17 Intron6 (NM_153211.1) A G A 0.33 0.29 rs6115865 20 3,307,303 C20orf194 −37687 bp (XM_045421) A G A 0.39 0.33 rs1467913 3 50,500,021 CACNA2D2 Intron2 (NM_006030.1) A C A 0.57 0.52 rs6786523 3 50,499,225 CACNA2D2 Intron2 (NM_006030.1) A G A 0.57 0.52 rs12494849 1 50,499,562 CACNA2D2 Intron2 (NM_006030.1) C G C 0.57 0.52 rs7571760 2 37,654,409 CDC42EP3 +127985 bp (NM_006449.3) A G A 0.40 0.35 rs10130333 14 88,929,499 CHES1 Intron2 (NM_005197.1) A C A 0.66 0.64 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs429419 0.002845 Allele 1.41 1.1-1.8 SEQ ID No: 239 SEQ ID No: 240 SEQ ID No: 536 SEQ ID No: 674 rs818725 0.003115 Allele 1.41 1.1-1.8 SEQ ID No: 241 SEQ ID No: 242 SEQ ID No: 537 SEQ ID No: 675 rs10902569 0.004911 Recessive 1.60 1.2-2.2 SEQ ID No: 243 SEQ ID No: 244 SEQ ID No: 538 rs2387658 0.001798 Recessive 1.39 1.1-1.7 SEQ ID No: 245 SEQ ID No: 246 SEQ ID No: 539 rs9881866 0.006808 Allele 1.35 1.1-1.7 SEQ ID No: 247 SEQ ID No: 248 SEQ ID No: 540 rs1342022 0.000210 Recessive 1.51 1.2-1.9 SEQ ID No: 249 SEQ ID No: 250 SEQ ID No: 541 rs6097745 0.006893 Dominant 1.32 1.1-1.6 SEQ ID No: 251 SEQ ID No: 252 SEQ ID No: 542 rs2816632 0.002470 Allele 1.33 1.1-1.6 SEQ ID No: 253 SEQ ID No: 254 SEQ ID No: 543 rs16940484 0.005060 Allele 1.25 1.1-1.5 SEQ ID No: 255 SEQ ID No: 256 SEQ ID No: 544 rs6115865 0.000217 Dominant 1.47 1.2-1.8 SEQ ID No: 257 SEQ ID No: 258 SEQ ID No: 545 rs1467913 0.001774 Dominant 1.49 1.2-1.9 SEQ ID No: 259 SEQ ID No: 260 SEQ ID No: 546 rs6786523 0.001906 Dominant 1.49 1.2-1.9 SEQ ID No: 261 SEQ ID No: 262 SEQ ID No: 547 rs12494849 0.005312 Allele 1.23 1.1-1.4 SEQ ID No: 263 SEQ ID No: 264 SEQ ID No: 548 SEQ ID No: 676 rs7571760 0.000490 Recessive 1.68 1.3-2.2 SEQ ID No: 265 SEQ ID No: 266 SEQ ID No: 549 rs10130333 0.005714 Dominant 1.53 1.1-2.1 SEQ ID No: 267 SEQ ID No: 268 SEQ ID No: 550

TABLE 54 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs493622 11 89,882,297 CHORDC1 −286443 bp (NM_012124.1) A C A 0.81 0.76 rs562160 11 89,887,386 CHORDC1 −291532 bp (NM_012124.1) A G G 0.81 0.76 rs2139539 1 31,786,872 COL16A1 +69 bp (NM_001856.2) A G G 0.84 0.80 rs909002 1 31,808,728 COL16A1 Intron44 (NM_001856.2) A G G 0.81 0.77 rs7902091 10 68,268,298 CTNNA3 Intron7 (NM_013266.1) A C A 0.50 0.45 rs2233476 3 50,363,387 CYB561D2 Exon1 (NM_007022.3) A C A 0.52 0.46 rs7676755 4 187,490,196 CYP4V2 Intron2 (NM_207352.1) C G C 0.81 0.80 rs3862680 18 48,184,338 DCC Intron1 (NM_005215.1) A C A 0.58 0.53 rs3862681 18 48,184,688 DCC Intron1 (NM_005215.1) A G A 0.58 0.53 rs11737784 4 84,300,869 DKFZp686L1814 −11708 bp (NM_194282.1) A C C 0.79 0.76 rs13137759 4 84,262,335 DKFZp686L1814 Intron2 (NM_194282.1) A G A 0.79 0.76 rs12700287 7 21,385,860 DNAH11 Intron8 (NM_003777.1) C G C 0.95 0.93 rs5765558 22 44,363,516 E46L −24767 bp (NM_013236.1) A G A 0.58 0.53 rs4823324 22 44,558,660 E46L Intron10 (NM_013236.1) A G A 0.50 0.45 rs1892116 1 243,406,363 ELYS Intron2 (NM_175865.1), A G A 0.75 0.70 ELYS Intron2 (NM_015446.1) Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs493622 0.000467 Allele 1.36 1.1-1.6 SEQ ID No: 269 SEQ ID No: 270 SEQ ID No: 551 rs562160 0.000696 Allele 1.35 1.1-1.6 SEQ ID No: 271 SEQ ID No: 272 SEQ ID No: 552 rs2139539 0.008566 Dominant 2.36 1.2-4.5 SEQ ID No: 273 SEQ ID No: 274 SEQ ID No: 553 rs909002 0.002649 Dominant 2.26 1.3-3.9 SEQ ID No: 275 SEQ ID No: 276 SEQ ID No: 554 rs7902091 0.001835 Recessive 1.47 1.2-1.9 SEQ ID No: 277 SEQ ID No: 278 SEQ ID No: 555 rs2233476 0.000169 Dominant 1.55 1.2-1.9 SEQ ID No: 279 SEQ ID No: 280 SEQ ID No: 556 rs7676755 0.006756 Dominant 1.96 1.2-3.2 SEQ ID No: 281 SEQ ID No: 282 SEQ ID No: 557 SEQ ID No: 677 rs3862680 0.002299 Allele 1.25 1.1-1.4 SEQ ID No: 283 SEQ ID No: 284 SEQ ID No: 558 rs3862681 0.002675 Allele 1.25 1.1-1.4 SEQ ID No: 285 SEQ ID No: 286 SEQ ID No: 559 rs11737784 0.007584 Recessive 1.32 1.1-1.6 SEQ ID No: 287 SEQ ID No: 288 SEQ ID No: 560 rs13137759 0.008987 Recessive 1.32 1.1-1.6 SEQ ID No: 289 SEQ ID No: 290 SEQ ID No: 561 rs12700287 0.005463 Allele 1.54 1.1-2.1 SEQ ID No: 291 SEQ ID No: 292 SEQ ID No: 562 SEQ ID No: 678 rs5765558 0.003829 Allele 1.24 1.1-1.4 SEQ ID No: 293 SEQ ID No: 294 SEQ ID No: 563 rs4823324 0.003204 Allele 1.24 1.1-1.4 SEQ ID No: 295 SEQ ID No: 296 SEQ ID No: 564 rs1892116 0.002178 Allele 1.28 1.1-1.5 SEQ ID No: 297 SEQ ID No: 298 SEQ ID No: 565

TABLE 55 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs9398995 6 132,181,896 ENPP1 Intron1 (NM_006208.1) A G A 0.56 0.52 rs1441354 15 69,517,251 FLJ13710 −290691 bp (NM_024817.1) A T T 0.27 0.27 rs1012728 3 21,319,300 FLJ22419 Intron4 (NM_024697.1) A C C 0.48 0.43 rs3922704 3 112,983,875 FLJ31579 Intron3 (NM_153268.1) C G G 0.88 0.83 rs1382851 12 25,689,829 FLJ36004 −92384 bp (NM_152590.1) A C C 0.57 0.53 rs4144951 15 51,643,802 FLJ38736 Intron17 (NM_182758.1) A G A 0.14 0.11 rs11750584 5 41,129,616 FLJ40243 −22454 bp (NM_173489.2) C G C 0.20 0.16 rs9300981 13 104,440,279 G30 +469126 bp (XM_498445) A C C 0.64 0.59 rs9640055 7 7,802,756 GLCCI1 Intron1 (XM_166529) A G A 0.82 0.79 rs9852677 3 50,266,621 GNA12 Intron4 (NM_002070.1) A G A 0.54 0.47 rs2236944 3 50,267,197 GNA12 Intron4 (NM_002070.1) A C A 0.52 0.46 rs610160 11 105,202,105 GR1A4 Intron3 (NM_000829.1) A G G 0.20 0.15 rs9498701 6 102,336,911 GRIK2 Intron6 (NM_021956.2), A G A 0.59 0.54 GRIK2 Intron6 (NM_175768.1) rs4840196 6 102,359,320 GRIK2 Intron8 (NM_021956.2), A T A 0.59 0.54 GRIK2 Intron8 (NM_175768.1) rs4840195 6 102,359,490 GRIK2 Intron8 (NM_021956.2), A G G 0.58 0.54 GRIK2 Intron8 (NM_175768.1) Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs9398995 0.008585 Recessive 1.35 1.1-1.7 SEQ ID No: 299 SEQ ID No: 300 SEQ ID No: 566 rs1441354 0.003800 Recessive 1.92 1.2-3  SEQ ID No: 301 SEQ ID No: 302 SEQ ID No: 567 SEQ ID No: 679 rs1012728 0.001063 Dominant 1.44 1.2-1.8 SEQ ID No: 303 SEQ ID No: 304 SEQ ID No: 568 rs3922704 0.000294 Allele 1.46 1.2-1.8 SEQ ID No: 305 SEQ ID No: 306 SEQ ID No: 569 SEQ ID No: 680 rs1382851 0.003765 Dominant 1.45 1.1-1.9 SEQ ID No: 307 SEQ ID No: 308 SEQ ID No: 570 rs4144951 0.005496 Dominant 1.42 1.1-1.8 SEQ ID No: 309 SEQ ID No: 310 SEQ ID No: 571 rs11750584 0.005023 Allele 1.31 1.1-1.6 SEQ ID No: 311 SEQ ID No: 312 SEQ ID No: 572 SEQ ID No: 681 rs9300981 0.005027 Dominant 1.50 1.1-2  SEQ ID No: 313 SEQ ID No: 314 SEQ ID No: 573 rs9640055 0.003780 Allele 1.30 1.1-1.6 SEQ ID No: 315 SEQ ID No: 316 SEQ ID No: 574 rs9852677 0.000278 Allele 1.30 1.1-1.5 SEQ ID No: 317 SEQ ID No: 318 SEQ ID No: 575 rs2236944 0.000383 Dominant 1.51 1.2-1.9 SEQ ID No: 319 SEQ ID No: 320 SEQ ID No: 576 rs610160 0.002530 Allele 1.34 1.1-1.6 SEQ ID No: 321 SEQ ID No: 322 SEQ ID No: 577 rs9498701 0.000935 Recessive 1.45 1.2-1.8 SEQ ID No: 323 SEQ ID No: 324 SEQ ID No: 578 rs4840196 0.001162 Recessive 1.44 1.2-1.8 SEQ ID No: 325 SEQ ID No: 326 SEQ ID No: 579 SEQ ID No: 682 rs4840195 0.001597 Recessive 1.43 1.1-1.8 SEQ ID No: 327 SEQ ID No: 328 SEQ ID No: 580

TABLE 56 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs9322609 6 102,357,540 GRIK2 Intron8 (NM_021956.2), A G G 0.58 0.54 GRIK2 Intron8 (NM_175768.1) rs2764236 6 102,389,150 GRIK2 Intron9 (NM_021956.2), A G A 0.59 0.54 GRIK2 Intron9 (NM_175768.1) rs779701 3 7,493,772 GRM7 Intron7 (NM_181875.1), A G G 0.33 0.28 GRM7 Intron7 (NM_000844.2), GRM7 Intron7 (NM_181874.1) rs4430902 2 189,010,443 GULP1 Intron1 (NM_016315.1) A G A 0.84 0.82 rs10271531 7 80,758,592 HGF +217504 bp (NM_000601.3) A G A 0.41 0.36 rs4430896 2 23,246,431 KBTBD9 −239670 bp (XM_496546) A G A 0.74 0.69 rs17279573 4 154,937,893 KIAA0922 +22425 bp (NM_015196.2) A G A 0.72 0.67 rs1206153 6 97,652,757 KIAA1900 Intron6 (NM_052904.1) A G A 0.53 0.50 rs4763559 12 10,622,909 KLRA1 +10130 bp (NM_006611.1) C G G 0.75 0.70 rs2125094 12 10,622,012 KLRA1 +11027 bp (NM_006611.1) A G G 0.74 0.69 rs11056970 12 16,558,431 LMO3 +34143 bp (NM_018640.3), A C C 0.85 0.82 LMO3 +34143 bp (NM_001001395.1) rs8086430 18 20,600,317 LOC147468 +250079 bp (XM_091809) A G G 0.27 0.23 rs7910849 10 31,144,546 LOC220929 +29028 bp (NM_182755.1) A G A 0.73 0.68 rs1462840 3 118,345,185 LOC285194 +426618 bp (XM_379207) A G G 0.62 0.56 rs7612549 3 34,789,105 LOC285307 +209732 bp (XM_211837) A C C 0.42 0.39 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs9322609 0.001827 Recessive 1.42 1.1-1.8 SEQ ID No: 329 SEQ ID No: 330 SEQ ID No: 581 rs2764236 0.001904 Recessive 1.42 1.1-1.8 SEQ ID No: 331 SEQ ID No: 332 SEQ ID No: 582 rs779701 0.002130 Allele 1.28 1.1-1.5 SEQ ID No: 333 SEQ ID No: 334 SEQ ID No: 583 rs4430902 0.009243 Recessive 1.33 1.1-1.7 SEQ ID No: 335 SEQ ID No: 336 SEQ ID No: 584 rs10271531 0.004906 Allele 1.23 1.1-1.4 SEQ ID No: 337 SEQ ID No: 338 SEQ ID No: 585 rs4430896 0.008596 Allele 1.24 1.1-1.4 SEQ ID No: 339 SEQ ID No: 340 SEQ ID No: 586 rs17279573 0.000685 Allele 1.31 1.1-1.5 SEQ ID No: 341 SEQ ID No: 342 SEQ ID No: 587 rs1206153 0.001009 Recessive 1.47 1.2-1.9 SEQ ID No: 343 SEQ ID No: 344 SEQ ID No: 588 rs4763559 0.000624 Allele 1.32 1.1-1.5 SEQ ID No: 345 SEQ ID No: 346 SEQ ID No: 589 SEQ ID No: 683 rs2125094 0.001004 Allele 1.30 1.1-1.5 SEQ ID No: 347 SEQ ID No: 348 SEQ ID No: 590 rs11056970 0.002381 Dominant 2.07 1.3-3.3 SEQ ID No: 349 SEQ ID No: 350 SEQ ID No: 591 rs8086430 0.006316 Allele 1.26 1.1-1.5 SEQ ID No: 351 SEQ ID No: 352 SEQ ID No: 592 rs7910849 0.000272 Recessive 1.46 1.2-1.8 SEQ ID No: 353 SEQ ID No: 354 SEQ ID No: 593 rs1462840 0.000975 Dominant 1.57 1.2-2.1 SEQ ID No: 355 SEQ ID No: 356 SEQ ID No: 594 rs7612549 0.005641 Recessive 1.49 1.1-2  SEQ ID No: 357 SEQ ID No: 358 SEQ ID No: 595

TABLE 57 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs6550308 3 34,911,573 LOC285307 +332200 bp (XM_211837) A G G 0.46 0.40 rs10517578 4 155,005,757 LOC285533 Intron4 (NM_173662.1) A G G 0.74 0.69 rs6468360 8 29,863,536 LOC286135 −35034 bp (XM_379573) C G C 0.55 0.52 rs2040073 1 38,498,317 LOC339442 −148785 bp (XM_378855) A G A 0.35 0.30 rs6431929 2 8,255,994 LOC339789 +41877 bp (NM_207358.1) A G G 0.69 0.66 rs10488110 7 9,827,710 LOC340268 Intron1 (XM_294634) A G G 0.11 0.07 rs411102 9 99,196,524 LOC347265 +48076 bp (XM_294590) A G A 0.14 0.10 rs782394 10 130,349,442 LOC387721 −251645 bp (XM_370585) A T A 0.53 0.49 rs10430126 1 47,934,070 LOC388630 +22072 bp (XM_371250) A C C 0.63 0.58 rs4668312 2 171,432,334 LOC389059 −20365 bp (XM_374017) A G A 0.73 0.68 rs6433243 2 171,431,002 LOC389059 −21697 bp (XM_374017) A G G 0.73 0.68 rs10184230 2 171,427,641 LOC389059 −25058 bp (XM_374017) A G A 0.73 0.68 rs6746374 2 171,445,013 LOC389059 −7686 bp (XM_374017) A G A 0.73 0.68 rs10492680 13 39,702,836 LOC400123 −23647 bp (XM_378411) A G A 0.93 0.89 rs10228514 7 35,237,035 LOC401324 +47709 bp (XM_379484) A C A 0.82 0.79 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs6550308 0.000835 Dominant 1.44 1.2-1.8 SEQ ID No: 359 SEQ ID No: 360 SEQ ID No: 596 rs10517578 0.002228 Allele 1.28 1.1-1.5 SEQ ID No: 361 SEQ ID No: 362 SEQ ID No: 597 rs6468360 0.003998 Recessive 1.39 1.1-1.7 SEQ ID No: 363 SEQ ID No: 364 SEQ ID No: 598 SEQ ID No: 684 rs2040073 0.001364 Dominant 1.39 1.1-1.7 SEQ ID No: 365 SEQ ID No: 366 SEQ ID No: 599 rs6431929 0.004709 Dominant 1.59 1.2-2.2 SEQ ID No: 367 SEQ ID No: 368 SEQ ID No: 600 rs10488110 0.000465 Allele 1.59 1.2-2.1 SEQ ID No: 369 SEQ ID No: 370 SEQ ID No: 601 rs411102 0.000158 Dominant 1.60 1.3-2.1 SEQ ID No: 371 SEQ ID No: 372 SEQ ID No: 602 rs782394 0.001769 Recessive 1.46 1.2-1.8 SEQ ID No: 373 SEQ ID No: 374 SEQ ID No: 603 SEQ ID No: 685 rs10430126 0.001484 Recessive 1.41 1.1-1.7 SEQ ID No: 375 SEQ ID No: 376 SEQ ID No: 604 rs4668312 0.001698 Allele 1.28 1.1-1.5 SEQ ID No: 377 SEQ ID No: 378 SEQ ID No: 605 rs6433243 0.001306 Allele 1.29 1.1-1.5 SEQ ID No: 379 SEQ ID No: 380 SEQ ID No: 606 rs10184230 0.001306 Allele 1.29 1.1-1.5 SEQ ID No: 381 SEQ ID No: 382 SEQ ID No: 607 rs6746374 0.001303 Allele 1.29 1.1-1.5 SEQ ID No: 383 SEQ ID No: 384 SEQ ID No: 608 rs10492680 0.000655 Allele 1.55 1.2-2  SEQ ID No: 385 SEQ ID No: 386 SEQ ID No: 609 rs10228514 0.009024 Recessive 1.33 1.1-1.6 SEQ ID No: 387 SEQ ID No: 388 SEQ ID No: 610

TABLE 58 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs17157033 10 44,613,470 LOC439960 −30545 bp (XM_498478) A C A 0.96 0.93 rs4307718 11 23,320,437 LOC440033 +175532 bp (XM_498512) A C C 0.95 0.93 rs6550783 3 23,719,090 LOC440947 −8191 bp (XM_496633) A G A 0.68 0.63 rs16891164 4 14,590,288 LOC441009 +88767 bp (XM_498965) A T T 0.95 0.93 rs339858 18 20,466,188 LOC441816 −124776 bp (XM_497584) A G A 0.15 0.11 rs17187933 11 20,556,033 LOC441816 −214621 bp (XM_497584) A G G 0.25 0.20 rs11876045 18 20,564,102 LOC441816 −222690 bp (XM_497584) C G C 0.26 0.22 rs17260163 18 20,592,187 LOC441816 −250775 bp (XM_497584) A G G 0.27 0.23 rs2004243 8 143,815,988 LOC51337 +641 bp (NM_016647.1) A G A 0.43 0.37 rs1990702 2 169,802,022 LRP2 +8346 bp (NM_004525.1) A G A 0.69 0.64 rs16883860 6 36,110,440 MAPK14 Intron1 (NM_139013.1), A G A 0.92 0.89 MAPK14 Intron1 (NM_001315.1), MAPK14 Intron1 (NM_139012.1), MAPK14 Intron1 (NM_139014.1) rs7761118 6 36,176,281 MAPK14 Intron9 (NM_139013.1), A G G 0.92 0.89 MAPK14 Intron9 (NM_001315.1), MAPK14 Intron9 (NM_139012.1), MAPK14 Intron9 (NM_139014.1) rs2359112 1 34,548,776 MGC15882 +194951 bp (NM_032884.2) A G A 0.33 0.31 rs16904092 8 130,571,112 MGC27434 Intron1 (NM_145050.2) A G A 0.90 0.88 rs10764881 10 131,153,821 MGMT −70674 bp (NM_002412.1) A G G 0.69 0.64 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs171157033 0.004744 Recessive 1.61 1.2-2.2 SEQ ID No: 389 SEQ ID No: 390 SEQ ID No: 611 rs4307718 0.009971 Allele 1.51 1.1-2.1 SEQ ID No: 391 SEQ ID No: 392 SEQ ID No: 612 rs6550783 0.003108 Allele 1.25 1.1-1.5 SEQ ID No: 393 SEQ ID No: 394 SEQ ID No: 613 rs16891164 0.003660 Allele 1.56 1.2-2.1 SEQ ID No: 395 SEQ ID No: 396 SEQ ID No: 614 SEQ ID No: 686 rs339858 0.007997 Allele 1.34 1.1-1.7 SEQ ID No: 397 SEQ ID No: 398 SEQ ID No: 615 rs17187933 0.002141 Dominant 1.39 1.1-1.7 SEQ ID No: 399 SEQ ID No: 400 SEQ ID No: 616 rs11876045 0.003407 Dominant 1.36 1.1-1.7 SEQ ID No: 401 SEQ ID No: 402 SEQ ID No: 617 SEQ ID No: 687 rs17260163 0.406099 Allele 1.26 1.1-1.5 SEQ ID No: 403 SEQ ID No: 404 SEQ ID No: 618 rs2004243 0.001099 Allele 1.27 1.1-1.5 SEQ ID No: 405 SEQ ID No: 406 SEQ ID No: 619 rs1990702 0.004527 Allele 1.24 1.1-1.4 SEQ ID No: 407 SEQ ID No: 408 SEQ ID No: 620 rs16883860 0.002150 Allele 1.46 1.1-1.9 SEQ ID No: 409 SEQ ID No: 410 SEQ ID No: 621 rs7761118 0.004398 Allele 1.42 1.1-1.8 SEQ ID No: 411 SEQ ID No: 412 SEQ ID No: 622 rs2359112 0.004022 Recessive 1.74 1.2-2.5 SEQ ID No: 413 SEQ ID No: 414 SEQ ID No: 623 rs16904092 0.007732 Recessive 1.41 1.1-1.8 SEQ ID No: 415 SEQ ID No: 416 SEQ ID No: 624 rs10764881 0.001557 Dominant 1.78 1.2-2.5 SEQ ID No: 417 SEQ ID No: 418 SEQ ID No: 625

TABLE 59 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs11016249 10 130,138,328 MK167 −323870 bp (NM_002417.2) A G G 0.68 0.64 rs2857648 22 28,391,122 NF2 Intron10 (NM_181825.1), C G G 0.71 0.67 NF2 Intron8 (NM_181831.1), NF2 Intron10 (NM_000268.2), NF2 Intron10 (NM_016418.4), NF2 Intron11 (NM_181826.1), NF2 Intron10 (NM_181827.1), NF2 Intron9 (NM_181828.1), NF2 Intron9 (NM_181829.1), NF2 Intron8 (NM_181830.1), NF2 Intron10 (NM_181832.1), NF2 Intron4 (NM_181833.1), NF2 Intron5 (NM_181834.1), NF2 Intron8 (NM_181835.1) rs17808998 17 8,919,071 NTN1 Intron2 (NM_004822.1) A G G 0.62 0.58 rs2072133 12 111,871,980 OAS3 Exon16 (NM_006187.2) A G A 0.66 0.61 rs4666488 2 19,608,777 ODD −128777 bp (NM_145260.1) A G A 0.38 0.33 rs10798882 1 31,777,640 PEF Intron1 (NM_012392.1) C G G 0.85 0.81 rs17754672 2 64,312,259 PELJ1 −61125 bp (NM_020651.2) A G A 0.22 0.18 rs10116231 9 78,151,153 PSAT1 Intron5 (NM_021154.3), A G G 0.76 0.71 PSAT1 Intron5 (NM_058179.2) rs2236913 1 223,380,860 PSEN2 Intron5 (NM_000447.1), A G G 0.37 0.34 PSEN2 Intron5 (NM_012486.1) rs7574012 2 37,638,881 QPCT +126765 bp (NM_012413.2) A G G 0.41 0.36 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs11016249 0.008687 Allele 1.22 1.1-1.4 SEQ ID No: 419 SEQ ID No: 420 SEQ ID No: 626 rs2857648 0.006985 Recessive 1.32 1.1-1.6 SEQ ID No: 421 SEQ ID No: 422 SEQ ID No: 627 SEQ ID No: 688 rs17808998 0.008779 Recessive 1.33 1.1-1.6 SEQ ID No: 423 SEQ ID No: 424 SEQ ID No: 628 rs2072133 0.003090 Allele 1.25 1.1-1.4 SEQ ID No: 425 SEQ ID No: 426 SEQ ID No: 629 rs4666488 0.000309 Dominant 1.46 1.2-1.8 SEQ ID No: 427 SEQ ID No: 428 SEQ ID No: 630 rs10798882 0.001679 Allele 1.36 1.1-1.6 SEQ ID No: 429 SEQ ID No: 430 SEQ ID No: 631 SEQ ID No: 689 rs17754672 0.006631 Recessive 2.36 1.3-4.4 SEQ ID No: 431 SEQ ID No: 432 SEQ ID No: 632 rs10116231 0.003816 Allele 1.27 1.1-1.5 SEQ ID No: 433 SEQ ID No: 434 SEQ ID No: 633 rs2236913 0.009042 Dominant 1.32 1.1-1.6 SEQ ID No: 435 SEQ ID No: 436 SEQ ID No: 634 rs7574012 0.001545 Recessive 1.59 1.2-2.1 SEQ ID No: 437 SEQ ID No: 438 SEQ ID No: 635

TABLE 60 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs6724538 2 37,639,669 QPCT +127553 bp (NM_012413.2) A C A 0.41 0.35 rs7584987 2 37,641,805 QCPT +129689 bp (NM_012413.2) A G G 0.44 0.39 rs1877823 17 60,657,405 RGS9 +3136 bp (NM_003835.1) A G A 0.77 0.74 rs9896245 17 60,604,218 RGS9 −11066 bp (NM_003835.1) A G A 0.74 0.71 rs1877821 17 60,605,875 RGS9 −9409 bp (NM_003835.1) A G G 0.74 0.72 rs16865980 2 7,255,254 RNF144 +120346 bp (NM_014746.2) A G A 0.25 0.21 rs9788983 17 129,457 RPH3AL Intron6 (NM_006987.2) A G A 0.88 0.84 rs17115925 14 81,341,217 SEL1L −271331 bp (NM_005065.3) A T T 0.73 0.70 rs1571379 14 81,359,690 SEL1L −289804 bp (NM_005065.3) A G A 0.73 0.67 rs12632110 3 50,199,229 SEMA3F Intron18 (NM_004186.2) A G A 0.52 0.47 rs1951626 1 170,623,758 SERPINC1 −5704 bp (NM_000488.1) A G A 0.36 0.31 rs2044757 3 155,352,950 SGEF Intron5 (NM_015595.2) A G G 0.64 0.61 rs33954719 3 155,359,077 SGEF Intron6 (NM_015595.2) A G A 0.64 0.61 rs3761960 6 36,101,884 SLC26A8 −1529 bp (NM_052961.2), A G A 0.92 0.89 SLC26A8 −1636 bp (NM_138718.1) rs1606405 13 82,684,518 SLITRK1 +664827 bp (NM_052910.1) A G A 0.54 0.50 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs6724538 0.000321 Recessive 1.69 1.3-2.2 SEQ ID No: 439 SEQ ID No: 440 SEQ ID No: 636 rs7584987 0.000572 Recessive 1.60 1.2-2.1 SEQ ID No: 441 SEQ ID No: 442 SEQ ID No: 637 rs1877823 0.001810 Dominant 1.98 1.3-3  SEQ ID No: 443 SEQ ID No: 444 SEQ ID No: 638 rs9896245 0.000141 Dominant 2.19 1.5-3.3 SEQ ID No: 445 SEQ ID No: 446 SEQ ID No: 639 rs1877821 0.000419 Dominant 2.10 1.4-3.2 SEQ ID No: 447 SEQ ID No: 448 SEQ ID No: 640 rs16865980 0.000687 Dominant 1.43 1.2-1.8 SEQ ID No: 449 SEQ ID No: 450 SEQ ID No: 641 rs9788983 0.000691 Allele 1.42 1.2-1.7 SEQ ID No: 451 SEQ ID No: 452 SEQ ID No: 642 rs17115925 0.009837 Allele 1.23 1.1-1.4 SEQ ID No: 453 SEQ ID No: 454 SEQ ID No: 643 SEQ ID No: 690 rs1571379 0.000529 Allele 1.32 1.1-1.5 SEQ ID No: 455 SEQ ID No: 456 SEQ ID No: 644 rs12632110 0.000586 Dominant 1.50 1.2-1.9 SEQ ID No: 457 SEQ ID No: 458 SEQ ID No: 645 rs1951626 0.009171 Allele 1.22 1.1-1.4 SEQ ID No: 459 SEQ ID No: 460 SEQ ID No: 646 rs2044757 0.001153 Dominant 1.61 1.2-2.1 SEQ ID No: 461 SEQ ID No: 462 SEQ ID No: 647 rs33954719 0.001078 Dominant 1.61 1.2-2.2 SEQ ID No: 463 SEQ ID No: 464 SEQ ID No: 648 rs3761960 0.002750 Allele 1.44 1.1-1.8 SEQ ID No: 465 SEQ ID No: 466 SEQ ID No: 649 rs1606405 0.002823 Recessive 1.42 1.1-1.8 SEQ ID No: 467 SEQ ID No: 468 SEQ ID No: 650

TABLE 61 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs2356232 2 171,412,281 SP5 +12276 bp (XM_371581) A G A 0.73 0.68 rs7608898 2 171,423,724 SP5 +23719 bp (XM_371581) A G A 0.73 0.68 rs10930437 2 171,406,848 SP5 +6843 bp (XM_371581) A G A 0.73 0.68 rs4667649 2 171,408,395 SP5 +8390 bp (XM_371581) A G A 0.73 0.68 rs2049723 11 13,922,920 SPON1 −17894 bp (NM_006108.1) A G A 0.74 0.69 rs2268794 2 31,691,055 SRD5A2 Intron1 (NM_000348.2) A T A 0.19 0.15 rs1106845 14 35,931,107 STELLAR +19768 bp (XM_375075) A T T 0.10 0.07 rs2966712 7 142,683,960 TAS2R41 −7843 bp (NM_176883.1) A G A 0.11 0.07 rs1658456 10 59,974,332 TFAM +148429 bp (NM_003201.1), A G G 0.58 0.53 TFAM +158914 bp (NM_012251.1) rs1649060 10 59,980,486 TFAM +154583 bp (NM_003201.1), C G C 0.58 0.53 TFAM +165068 bp (NM_012251.1) rs1649048 10 59,994,288 TFAM +168385 bp (NM_003201.1), A G G 0.58 0.53 TFAM +178870 bp (NM_012251.l) rs1658438 10 59,996,589 TFAM +170686 bp (NM_003201.1), A G G 0.58 0.52 TFAM +181171 bp (NM_012251.1) rs1649039 10 60,000,047 TFAM +174144 bp (NM_003201.1), A G G 0.57 0.52 TFAM +184629 bp (NM_012251.1) rs10763558 10 60,011,940 TFAM +186037 bp (NM_003201.1), A C C 0.57 0.52 TFAM +196522 bp (NM_012251.1) rs11727442 4 154,943,527 TLR2 −23144 bp (NM_003264.2) A G G 0.69 0.64 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary for Secondary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs2356232 0.001522 Allele 1.29 1.1-1.5 SEQ ID No: 469 SEQ ID No: 470 SEQ ID No: 651 rs7608898 0.001306 Allele 1.29 1.1-1.5 SEQ ID No: 471 SEQ ID No: 472 SEQ ID No: 652 rs10930437 0.001587 Allele 1.29 1.1-1.5 SEQ ID No: 473 SEQ ID No: 474 SEQ ID No: 653 rs4667649 0.001662 Allele 1.28 1.1-1.5 SEQ ID No: 475 SEQ ID No: 476 SEQ ID No: 654 rs2049723 0.002649 Allele 1.27 1.1-1.5 SEQ ID No: 477 SEQ ID No: 478 SEQ ID No: 655 rs2268794 0.006152 Allele 1.31 1.1-1.6 SEQ ID No: 479 SEQ ID No: 480 SEQ ID No: 656 SEQ ID No: 691 rs1106845 0.006141 Allele 1.45 1.1-1.9 SEQ ID No: 481 SEQ ID No: 482 SEQ ID No: 657 SEQ ID No: 692 rs2966712 0.000304 Dominant 1.66 1.3-2.2 SEQ ID No: 483 SEQ ID No: 484 SEQ ID No: 658 rs1658456 0.006414 Allele 1.22 1.1-1.4 SEQ ID No: 485 SEQ ID No: 486 SEQ ID No: 659 rs1649060 0.006414 Allele 1.22 1.1-1.4 SEQ ID No: 487 SEQ ID No: 488 SEQ ID No: 660 SEQ ID No: 693 rs1649048 0.006480 Allele 1.22 1.1-1.4 SEQ ID No: 489 SEQ ID No: 490 SEQ ID No: 661 rs1658438 0.006270 Allele 1.22 1.1-1.4 SEQ ID No: 491 SEQ ID No: 492 SEQ ID No: 662 rs1649039 0.007438 Allele 1.22 1.1-1.4 SEQ ID No: 493 SEQ ID No: 494 SEQ ID No: 663 rs10763558 0.008997 Allele 1.21  1-1.4 SEQ ID No: 495 SEQ ID No: 496 SEQ ID No: 664 rs11727442 0.000624 Recessive 1.43 1.2-1.8 SEQ ID No: 497 SEQ ID No: 498 SEQ ID No: 665

TABLE 62 High-Risk High-Risk Allele Allele High- Frequency in Frequency in Chromo- Physical Allele Allele Risk Glaucoma Non-Patient dBSNP ID some Location Exon, Intron 1 2 Allele Patient Group Group rs3804100 4 154,983,014 TLR2 Exon2 (NM_003264.2) A C A 0.73 0.68 rs1028534 10 51,898,627 TMEM23 Intron3 (NM_147156.3) A C C 0.63 0.60 rs1210065 10 51,882,795 TMEM23 Intron5 (NM_147156.3) A G A 0.40 0.35 rs17473451 8 15,368,500 TUSC3 −73601 bp (NM_006765.2), C G C 0.76 0.72 TUSC3 −73601 bp (NM_178234.1) rs6829490 4 47,908,795 TXK +894 bp (NM_003328.1) A G G 0.54 0.49 rs500629 11 113,550,770 ZBTB16 Intron3 (NM_006006.3) A C C 0.28 0.23 rs2864107 19 56,760,839 ZNF175 −5504 bp (NM_007147.2) A G A 0.21 0.17 rs3755827 3 62,335,411 ZNF312 −1350 bp (NM_018008.2) A G A 0.79 0.74 Mantel- Mantel- Haenszel Haenszel 95% Sequence Sequence Sequence 1 Sequence 2 Test Test Odds Confidence Containing Containing for Secondary Seco forndary dBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probe rs3804100 0.003499 Allele 1.26 1.1-1.5 SEQ ID No: 499 SEQ ID No: 500 SEQ ID No: 666 rs1028534 0.005678 Dominant 1.48 1.1-2  SEQ ID No: 501 SEQ ID No: 502 SEQ ID No: 667 rs1210065 0.001850 Dominant 1.39 1.1-1.7 SEQ ID No: 503 SEQ ID No: 504 SEQ ID No: 668 rs17473451 0.003504 Recessive 1.35 1.1-1.7 SEQ ID No: 505 SEQ ID No: 506 SEQ ID No: 669 SEQ ID No: 694 rs6829490 0.009776 Dominant 1.37 1.1-1.7 SEQ ID No: 507 SEQ ID No: 508 SEQ ID No: 670 rs500629 0.001621 Dominant 1.39 1.1-1.7 SEQ ID No: 509 SEQ ID No: 510 SEQ ID No: 671 rs2864107 0.000428 Dominant 1.47 1.2-1.8 SEQ ID No: 511 SEQ ID No: 512 SEQ ID No: 672 rs3755827 0.004467 Allele 1.28 1.1-1.5 SEQ ID No: 513 SEQ ID No: 514 SEQ ID No: 673

The single nucleotide polymorphisms listed in Tables 53 to 62 can be also used as a marker for predicting an onset risk of glaucoma in the same manner.

Next, regions and/or genes of the surrounding of single nucleotide polymorphism listed in Table 52 were determined by making reference to the database provided by the HapMap project. In detail, regions in which the single nucleotide polymorphism considered to be in a linkage disequilibrium with the single nucleotide polymorphisms listed in Table 52 exists were determined, on the basis of the linkage disequilibrium data in combination of the Japanese and the Chinese in the HapMap project.

Also, in a case where the single nucleotide polymorphism listed in Table 52 exists in the linkage disequilibrium region containing genes, the physical location of the region and the gene name were determined. On the other hand, in a case where the single nucleotide polymorphism listed in Table 52 exists in the linkage disequilibrium region without containing the genes, only the physical location of the region was determined. In addition, in a case where the single nucleotide polymorphism listed in Table 52 exists on one gene beyond the linkage disequilibrium region, the gene name and the physical location of the gene were determined.

A single nucleotide polymorphism of which p-value is the lowest for each region is considered to be a single nucleotide polymorphism representing the region, and Tables 63 to 70 list a single nucleotide polymorphism representing the region, the chromosome number at which the region exists, the physical location of the region (start point and end point) and the gene name contained in the region.

TABLE 63 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Chro- Polymorphism with mo- Start End Genes in Lowest p-value) some Location Location the Region rs10798882 1 31,707,055 31,838,861 COL16A1 LCN7 HCRTR1 PEF1 rs2359112 1 34,477,408 34,552,678 — rs2040073 1 38,408,125 38,527,689 — rs10430126 1 47,930,338 48,198,192 — rs1951626 1 170,033,793 171,848,859 TNN MRPS14 CACYBP RABGAP1L RC3H1 SERPINC1 ZBTB37 DARS2 CENPL KLHL20 ANKRD45 SLC9A11 PRDX6 rs2236913 1 223,126,127 223,405,511 ITPKB PSEN2 rs693421 1 234,339,548 234,432,433 ZP4 rs1892116 1 243,319,348 243,497,348 ZNF695 ELYS AHCTF1 rs16865980 2 7,200,812 7,280,358 — rs6431929 2 8,187,182 8,419,147 LOC339789 rs4666488 2 19,472,875 19,608,452 OSR1 rs4430896 2 23,145,684 23,366,310 —

TABLE 64 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Chro- Polymorphism with mo- End Genes in Lowest p-value) some Start Location Location the Region rs2268794 2 31,468,839 33,038,731 XDH SRD5A2 MEMO1 DPY30 SPAST SLC30A6 NLRC4 YIPF4 BIRC6 TTC27 rs6724538 2 37,588,322 37,740,529 — rs17754672 2 62,704,890 64,419,622 EHBP1 OTX1 LOC51057 MDH1 UGP2 VPS54 PELI1 rs12611812 2 124,499,094 125,389,091 CNTNAP5 rs7559118 2 133,263,104 134,159,763 NAP5 FLJ34870 rs1990702 2 169,796,465 170,044,629 LRP2 rs6746374 2 171,322,396 171,550,925 AK127400 GAD1 SP5 LOC440925 rs4430902 2 188,685,976 189,579,329 GULP1 DIRC1 rs779701 3 6,877,927 7,758,217 GRM7 rs1012728 3 21,437,673 21,767,820 ZNF385D rs6550783 3 23,654,468 23,750,569 —

TABLE 65 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Chro- Polymorphism with mo- End Genes in Lowest p-value) some Start Location Location the Region rs6550308 3 34,785,788 35,165,798 — rs2233476 3 49,686,439 51,799,207 APEH MST1 RNF123 AMIGO3 GMPPB IHPK1 LOC389118 C3orf54 UBA7 TRAIP CAMKV MST1R MON1A RBM6 RBM5 SEMA3F GNAT1 SLC38A3 GNAI2 SEMA3B IFRD2 NAT6 C3orf45 HYAL3 HYAL1 HYAL2 TUSC2 RASSF1 ZMYND10 TUSC4 CYB561D2 TMEM115 CACNA2D2 C3orf18 HEMK1 CISH MAPKAPK3 DOCK3 ARMET REM15B VPRBP RAD54L2 TEX264 GRM2

TABLE 66 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Polymorphism Chro- with mo- Start End Genes in Lowest p-value) some Location Location the Region rs3755827 3 62,280,436 62,836,094 C3orf14 CADPS ZNF312 rs9881866 3 106,122,067 106,319,409 — rs3922704 3 112,876,213 113,177,795 PLCXD2 CR749654 AY358772 rs1462840 3 118,332,596 118,498,089 — rs33954719 3 155,198,039 155,457,039 SGEF rs16891164 4 14,149,949 14,598,571 BC036758 rs6829490 4 47,436,948 48,813,871 CORIN NFXL1 CNGA1 NPAL1 TXK TEC SLAIN2 ZAR1 FRYL OCIAD1 OCIAD2 rs10517556 4 62,191,605 63,083,785 LPHN3 rs11737784 4 83,907,869 84,368,310 SCD5 SEC31A THAP9 LIN54 COPS4 rs13110551 4 140,152,121 140,188,487 — rs11727442 4 154,745,157 155,130,602 KIAA0922 TLR2 RNF175 SFRP2 rs7676755 4 187,346,286 187,611,026 TLR3 DKFZP564J102 CYP4V2 KLKB1 F11

TABLE 67 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Polymorphism Chro- with mo- Start End Genes in Lowest p-value) some Location Location the Region rs429419 5 33,563,046 33,927,881 ADAMTS12 rs6451268 5 36,139,171 36,337,761 DKFZp434H2226 SKP2 FLJ30596 FLJ25422 rs11750584 5 41,033,879 41,298,707 FLJ40243 C6 rs9358578 6 22,707,365 22,854,322 LOC389370 rs16883860 6 36,015,011 36,252,339 SLC26A8 MAPK14 MAPK13 rs1206153 6 97,479,326 97,864,503 KIAA1900 C6orf167 rs9498701 6 101,953,626 102,624,651 GRIK2 rs9398995 6 132,000,135 132,286,336 ENPP3 ENPP1 rs9640055 7 7,772,656 8,075,425 ICA1 GLCCI1 rs10488110 7 9,768,215 9,875,870 — rs12700287 7 21,338,075 21,714,695 DNAH11 rs10228514 7 35,169,289 35,359,069 — rs10271531 7 80,612,379 80,941,240 — rs2966712 7 142,596,643 142,732,627 ZYX EPHA1 TAS2R60 TAS2R41 rs17473451 8 15,324,913 15,422,271 — rs6468360 8 29,800,821 29,866,436 — rs16935718 8 69,986,592 70,338,390 ratara. bAug05 swakoy.aAug05 LOC389667 rs16904092 8 130,556,102 130,700,866 —

TABLE 68 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Chro- Polymorphism with mo- End Genes in Lowest p-value) some Start Location Location the Region rs2004243 8 143,716,339 143,900,127 JRK PSCA LY6K C8orf55 SLURP1 LYNX1 LYPD2 LY6D rs1342022 9 72,743,457 72,939,880 ALDH1A1 rs10116231 9 78,136,500 78,174,561 PSAT1 rs411102 9 99,100,781 99,364,219 — rs7850541 9 132,883,652 133,218,347 GFI1B CR615294 GTF3C5 CEL CELP RALGDS GBGT1 OBP2B ABO rs2387658 10 1,218,073 1,769,718 ADARB2 rs7081455 10 20,662,930 20,719,326 — rs7910849 10 31,072,503 31,165,996 — rs17157033 10 44,456,300 44,698,295 — rs1210065 10 51,696,167 52,116,588 TMEM23 AK056520 rs1658438 10 59,803,487 60,258,851 BICC1 TFAM rs7902091 10 67,349,937 69,125,933 CTNNA3 rs11016249 10 129,959,024 130,173,385 — rs782394 10 130,233,084 130,350,260 — rs10764881 10 131,138,138 131,455,356 MGMT rs2049723 11 13,850,243 14,246,222 SPON1 rs4307718 11 23,202,964 23,481,112 —

TABLE 69 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Chro- Polymorphism with mo- End Genes in Lowest p-value) some Start Location Location the Region rs493622 11 89,679,112 90,004,712 — rs610160 11 104,896,113 105,358,029 GRIA4 rs500629 11 113,435,641 113,626,604 ZBTB16 rs4763559 12 10,539,469 10,726,280 KLRA1 FLJ10292 STYK1 rs11056970 12 16,468,226 16,587,335 — rs1382851 12 25,669,680 25,892,423 — rs7961953 12 81,537,331 82,030,531 TMTC2 rs2072133 12 111,807,459 111,912,247 OAS1 OAS2 OAS3 rs10492680 13 39,608,046 39,760,155 — rs1606405 13 82,325,708 82,739,954 BC016673 rs9300981 13 104,391,167 104,481,207 — rs1106845 14 35,808,124 35,947,704 MBIP rs1571379 14 81,213,431 81,378,859 — rs10130333 14 88,692,269 89,155,247 CHES1 rs2816632 14 104,746,671 104,838,374 BRF1 BTBD6 rs4144951 15 51,558,394 51,892,014 WDR72 rs1441354 15 69,220,842 69,862,776 THSD4 rs10902569 15 98,329,166 98,699,706 ADAMTS17 rs9788983 17 62,294 271,176 RPH3AL LOC400566 rs17808998 17 8,845,288 9,088,042 NTN1 rs9896245 17 60,532,473 60,654,283 RGS9 rs1877823 17 60,564,011 60,680,796 RGS9 rs16940484 18 19,826,735 20,231,788 C18orf17 OSBPL1A CABYR rs17187933 18 20,389,931 20,699,770 —

TABLE 70 Representative Single Nucleotide Polymorphism in the Region (Single Nucleotide Chro- Polymorphism with mo- End Genes in Lowest p-value) some Start Location Location the Region rs3862680 18 48,050,184 49,311,780 DCC rs2864107 19 56,686,425 56,784,802 SIGLEC12 ZNF175 SIGLEC6 rs6115865 20 3,156,064 3,351,824 SLC4A11 C20orf194 rs6097745 20 51,935,413 52,170,007 BCAS1 rs2857648 22 28,153,305 28,436,178 RFPL1 NEFH THOC5 NIPSNAP1 NF2 rs4823324 22 44,219,256 44,580,747 FBLN1 ATXN10

The region listed in Tables 63 to 70 is a region or gene considered to be linked with a single nucleotide polymorphism associated with the onset of glaucoma in the present invention listed in Tables 53 to 62, and a single nucleotide polymorphism which exists in these regions or genes is considered to be linked with a single nucleotide polymorphism in the present invention. In other words, any single nucleotide polymorphisms which exist in these regions are linked with the single nucleotide polymorphism which exists in the region listed in Tables 53 to 62, and any of these single nucleotide polymorphisms can be used in the prediction of an onset risk of glaucoma in the same manner.

Example 11 Logistic Regression Analysis

In the present invention, by combining any two or more single nucleotide polymorphisms determined to be involved in the onset of glaucoma, an extent to which the precision of the prediction of a risk of a disease improves is examined with logistic regression analysis, as compared to that where each of the single nucleotide polymorphisms is used alone. In the present analysis, any combinations of the single nucleotide polymorphisms determined to be significantly associated with the onset of glaucoma by statistically comparing allele or genotype frequencies can be used. In one example, 17 single nucleotide polymorphisms that showed a significant difference under the Bonferroni correction were subjected to the logistic regression analysis.

Out of 17 single nucleotide polymorphisms that had a significance under the Bonferroni correction, single nucleotide polymorphisms for use in the logistic regression analysis were further narrowed down according to a stepwise method. The value of 0.01 was adopted as criteria of variable incorporation and variable exclusion in the stepwise method. Upon the application of a stepwise method, a single nucleotide polymorphism belonging to the same LD block (ones having the same description in the column of linkage disequilibrium in Table 52) is represented by any one of single nucleotide polymorphisms belonging to each of the LD blocks, and it is set so that any one of the single nucleotide polymorphisms is to be a subject to be incorporated. Each of the narrowed-down single nucleotide polymorphisms is defined as an independent variable(Π) (homozygote of one allele=0, heterozygote=1, homozygote of opposite allele=2), and each regression coefficient (λ) can be determined according to the logistic regression analysis, and the following formula (18) was obtained.

Φ=1/{1+exp[−(λ0+λ1Π1+λ2Π2+λ3Π3+ . . . )]}  formula (18)

Next, in each sample, a value for risk prediction (Φ) was calculated by substituting a variable for each single nucleotide polymorphisms into this formula. When Φ is greater than 0.5, this sample donor was determined to be with an onset risk. A concordance rate was calculated by comparing the determination results with the matter of whether the sample donor having a single nucleotide polymorphism was actually a glaucoma patient. Further, the concordance rate was determined as mentioned above for each of the incorporated single nucleotide polymorphisms alone, and all the combinations of any two or more single nucleotide polymorphisms, and means and standard deviations of the concordance rate were obtained for each of the number of single nucleotide polymorphisms used in combination. Table 71 lists the number of single nucleotide polymorphisms, alone or in a combination of arbitrary number, the number of combinations when arbitrary number of single nucleotide polymorphism is combined, and the relationship between the mean and the standard deviation of the concordance rate. Here, all the calculations were performed using SAS 9.1.3, Windows (registered trademark) Edition, SAS Institute Japan Corporation.

As listed in Table 71, according to a stepwise method, out of the 17 single nucleotide polymorphisms, assuming that a pair of single nucleotide polymorphisms belonging to the same LD block were each counted as one, all ten single nucleotide polymorphisms were selected (rs7081455, rs693421, rs9358578, rs7961953, rs16935718, rsl 1123034, rs13110551, rs7559118, rs10517556, and rs6451268). A value for risk prediction (Φ) of individual cases was calculated using a logistic regression formula, alone or in a combination of any two or more of these 10 single nucleotide polymorphisms. When a cut-off value for a value for risk prediction is defined as 0.5, mean±standard deviation of the concordance rate was 54.7±1.4% in a case that each of the single nucleotide polymorphisms was used alone. This concordance rate was elevated as an increase in the number of single nucleotide polymorphisms used in combination, and reached the maximum of 59.9% in a case that all the ten were combined.

TABLE 71 The Number of The Number of Concordance Rate SNP Combination (Mean Value) Standard Deviation 1 10 54.7 1.4 2 45 55.7 1.1 3 120 56.3 1.0 4 210 57.0 1.0 5 252 57.5 1.0 6 210 58.0 1.0 7 120 58.4 1.0 8 45 58.8 1.0 9 10 59.1 0.9 10 1 59.9 —

As described above, it was evident that in the determination of an onset risk of glaucoma by a single nucleotide polymorphism, an excellent concordance rate can be obtained even in a case that each of the single nucleotide polymorphisms are used alone, and the diagnostic precision can be further enhanced by combining these single nucleotide polymorphisms.

As described above, an individual who has an allele or a genotype that is identified in a high frequency in the glaucoma patients disclosed in the present invention on the genome has a high onset risk of glaucoma in future, and an individual who does not have an allele or a genotype that is identified in a high frequency in the glaucoma patients has a low onset risk of glaucoma in future.

INDUSTRIAL APPLICABILITY

According to the method of the present invention, the level of an onset risk of glaucoma of a sample donor can be determined by analyzing an allele or a genotype of a single nucleotide polymorphism in the present invention in a sample. A sample donor can take a preventive measure of glaucoma, or can receive appropriate treatments, on the basis of this risk. In addition, it is useful because, a sample donor who has an allele or a genotype that is identified in a high frequency in the glaucoma patients of a single nucleotide polymorphism in the present invention on the genome can be given a precision examination in whether or not the donor is with an early glaucoma which is difficult to be determined sufficiently by an intraocular pressure or an ocular fundus photograph, and can be started with a treatment at an early stage in a case where the donor is diagnosed as glaucoma. 

1. A method of determining the presence or the absence of a glaucoma risk, comprising: A. detecting in vitro an allele and/or a genotype of a single nucleotide polymorphism which is located on a 31st base of a base sequence, in a sample from a subject, wherein the base sequence is at least one base sequence selected from the group consisting of SEQ ID NO: 275 and SEQ ID NO: 276 or a complementary sequence thereto, and B. comparing the allele and/or the genotype detected in with at least one of an allele and/or a genotype, comprising a high-risk allele, in SEQ ID NO: 275 and SEQ ID NO: 276, wherein the presence of a glaucoma risk is determined in a case where the allele detected in A is the high-risk allele, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in A is a homozygote of the genotype comprising the high-risk allele or a heterozygote when the high-risk allele complies with a dominant genetic model, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in A is a homozygote of the genotype comprising the high-risk allele when the high-risk allele complies with a recessive genetic model.
 2. The method according to claim 1, wherein the glaucoma risk is an onset risk of glaucoma.
 3. The method according to claim 2, wherein the base sequence is SEQ ID NO:
 275. 4. The method according to claim 3, wherein the comparison in B further comprises selecting and combining any two or more alleles and/or genotypes, comprising the high-risk allele, in the base sequences shown in SEQ ID NOs: 203 to 238, wherein the presence of a glaucoma risk is determined in a case where the allele detected in A is any one of the alleles selected for the comparison in B, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in A is a homozygote or a heterozygote of any one of the genotypes selected for the comparison in B when the high-risk allele complies with a dominant genetic model, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in A is a homozygote of any one of the genotypes selected for the comparison in B when the high-risk allele complies with a recessive genetic model.
 5. The method according to claim 4, wherein the comparison in B further comprises selecting and combining all the alleles and/or the genotypes, comprising the high-risk allele, in the base sequences shown in SEQ ID NOs: 203 to 238, wherein the presence of a glaucoma risk is determined in a case where the allele detected in A is any one of the alleles selected for the comparison in B, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in A is a homozygote or a heterozygote of any one of the genotypes selected for the comparison in the B when the high-risk allele complies with a dominant genetic model, or wherein the presence of a glaucoma risk is determined in a case where the genotype detected in A is a homozygote of any one of the genotypes selected for the comparison in B when the high-risk allele complies with a recessive genetic model.
 6. The method according to claim 2, further comprising predicting the level of the onset risk.
 7. The method according to claim 1, wherein the glaucoma is primary open-angle glaucoma (POAG) or normal tension glaucoma (NTG). 8-27. (canceled)
 28. A method of determining the presence or the absence of a glaucoma risk, comprising: (i): extracting a nucleic acid molecule from a sample from a subject, (ii): detecting an allele of a single nucleotide polymorphism which is located on a 31st base of a base sequence, wherein the base sequence is at least one base sequence selected from the group consisting of SEQ ID NO: 275 and SEQ ID NO: 276 or a complementary sequence thereto, for the nucleic acid molecule extracted in (i), and (iii): determining the presence or the absence of a glaucoma risk, based on the allele detected in (ii).
 29. The method according to claim 28, wherein (iii) comprises determining a genotype, based on the allele detected in (ii).
 30. The method according to claim 28, wherein (iii) comprises the step of determining whether or not the allele detected in (ii) is a high-risk allele.
 31. The method according to claim 30, wherein (iii) comprises the step of determining that the glaucoma risk is high in a case where the allele detected in (ii) is the high-risk allele. 32-34. (canceled)
 35. The method according to claim 2, wherein the base sequence is SEQ ID NO:
 276. 36. The method according to claim 28, wherein the base sequence is SEQ ID NO:
 275. 37. The method according to claim 28, wherein the base sequence is SEQ ID NO:
 276. 